EA032642B1 - PYRIDINO[1,2-a]PYRIMIDONE ANALOGUES USED AS PI3K INHIBITORS - Google Patents

Abstract

Disclosed are pyridino[1,2-a]pyrimidone analogues used as PI3K inhibitors. The present invention particularly relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

The invention relates to the class of pyrido [1,2-a] pyrimidone analogues as ΡΙ3Κ inhibitors and, more particularly, relates to a compound represented by formula (I), or a pharmaceutically acceptable salt thereof.

State of the art

The ΡΙ3Κ pathway is the most typical case when human cancer cells mutate, which can lead to cell proliferation, activation, and signal amplification. ΡΙ3Κ kinases (phosphatidylinositol-3-kinases, ΡΙ3Κ§) belong to the family of lipid kinases and are able to phosphorylate phosphatidylinositol at the 3'-OH end position of the inositol ring. Phosphatidylinositol-3-kinase (ΡΙ3Κ) is a lipid kinase consisting of the regulatory subunit p85 or p101 and the catalytic subunit p110. It catalyzes the phosphorylation of phosphatidylinositol-4,5bisphosphate (ΡΪΡ2) to form phosphatidylinositol-3,4,5-triphosphate (ΡΙΡ3), thereby activating the subsequent units of the Lk signaling cascade! etc., thus, playing a key role in proliferation, survival, cell metabolism and the like. Thus, inhibition of phosphatidylinositol-3-kinases can affect the ΡΙ3Κ pathway, thereby inhibiting the proliferation and activation of cancer cells.

The tumor suppressor gene ΡΤΕΝ (phosphatase and tensin homolog with deletion on chromosome 10) dephosphorylates ΡΙΡ3 to ΡΙΡ2, thereby achieving negative regulation of the ΡΙ3ΚΜΓΐ signaling pathway, inhibiting cell proliferation and stimulating cell apoptosis. Frequent cases of ΡΙ3Κ gene mutation and amplification in cancers, the absence of ΡΤΕΝ in cancerous tumors and the like show that ΡΙ3Κ is closely associated with the occurrence of cancerous tumors.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a compound represented by formula (Ι) or

where E is selected from the group consisting of C _1-6 alkyl, from 3 to 10 membered aryl, from 3 to 10 membered cycloalkyl, and from 3 to 10 membered heteroaryl, wherein said C _1-6 alkyl, from 3- to 10-membered aryl, 3- to 10-membered cycloalkyl or 3- to 10-membered heteroaryl are optionally substituted with 1, 2 or 3 Κ ₃ , and K _{3 is} selected from the group consisting of H, E, C1, Br, Ι, ΝΗ _2, and C _1-10 alkyl, wherein said 3 to 10 membered heteroaryl contains 1, 2, or 3 heteroatoms, each of which is independently selected from the group consisting of Ν, O, and 8;

one of b and P is selected from the group consisting of ^ (= Ο) ΝΗ-, -8 (= Ο) ₂ ΝΗ- and -ΝΗ ^ = Ο) ΝΗ-, and the other is selected from the group consisting of a single bond and - CH ₂ -; A is selected from the group Ν; X, Υ and Ζ are CH; t ₁ has a value of 1;

one of Κ _1-2 is

and the other is selected from the group consisting of H, E, C1, Br, Ι, XH ₂ , and C _1-10 alkoxy;

Ό _{1 is} selected from the group consisting of a single bond, -ΝΙI- and -O-;

Ό ₂ represents —C (K _a1 ) (Ka ₂ ) -, wherein said Κ _ά1 and Κ _{ά2 are} independently selected from the group consisting of H and C _1-10 alkyl;

Ό _{3 is} selected from the group consisting of -Ν (Κ _ά4 ) -, -ί.χ = Ο) Ν (Κ ₁₄ ) -, -Ν (Κ4 ₄ Λ (= Ο) -, -8 (= Ο) ₂ - and -8 (= Ο) ₂ Ν (Κ _ά6 ) -, where the indicated K ₄₄ and K _{46 are} independently selected from the group consisting of H and Κ ₀₂ ;

K _{4 is} selected from the group consisting of H, C _1-10 alkyl and C _1-10 heteroalkyl, wherein said C _1-10 alkyl and C _1-10 heteroalkyl are optionally substituted with Κ ₀₁ , where said C _1-10 heteroalkyl contains 1 or 2 heteroatoms or heteroatomic groups, each of which is independently selected from the group consisting of Ν, O, 8, C ^ N, C (= O) and -8 (= Ο) 2;

η is 1, 2, 3 or 4;

or any of K _a1 and K ₄₂ in the same Ό ₂ , two Ό ₂ , Κ ₄ and one Ό ₂ , or K ₄ and Ό _{3 are} attached together to the same carbon atom or heteroatom with the formation of one or two 3 -, 4-, 5- or 6-membered carbocyclic ring or 3-, 4-, 5- or 6-membered heterocyclic ring, where the specified heterocyclic ring contains 1, 2 or 3 heteroatoms or heteroatomic groups, each of which is independently selected from the group consisting of Ν, O, 8, ^^^ Н, С (= О) and -8 (= Ο) ₂ ;

Κοι is selected from the group consisting of E, C1, Br, Ι, ΟΙ I, 8H and Κ ₀₂ ;

Κ _{02 is} selected from the group consisting of C _1-10 alkyl, C _1-10 alkanoyl and C _1-10 alkylsulfonyl, wherein said Co _{2 is} optionally substituted with Κ ₀₀₁ , and Κο _{01 is} selected from the group consisting of E, C1, Br, Ι, ΟΙ I, XN ₂ , and

- 1,032,642 methoxy; and in any of the above cases, the amount of K ₀₁ or K _{001 of} each is independently 0, 1, 2, or 3.

In one of the embodiments of the present invention, E is selected from the group consisting of C _1-6 alkyl and C _3-6 cycloalkyl, or E is selected from the group consisting of

where O ₁ ~ 5 represent C (K ₃ );

O _{6 is} selected from the group consisting of -C (K ₃ ) (K ₃ ) - and -8-;

none or one O ₇ ~ ₉ represent N and others represent C (K ₃ ).

In one of the embodiments of the present invention, E is selected from the group consisting of methyl,

all of which are optionally substituted with 1, 2 or 3 K ₃ .

In one of the embodiments of the present invention, E is selected from the group consisting of

and methyl, all of which are optionally substituted with 1, 2 or 3 halogen atoms, ΝΗ ₂ and C _1-3 alkyl.

In one embodiment of the present invention, E is selected from the group consisting of 'E

E

E

C1 C1

C1

R

C1

E

E

I

E

In one of the embodiments of the present invention, the ring formed between any of Κ _{ά 1} and K _a2 in the same Ό ₂ , two Ό ₂ , Cd and one Ό ₂ , or Cd and Ό ₃ , is selected from the group consisting of

all of which are optionally substituted with 1 or 2 halogens, OH, ΝΗ ₂ , C _1-3 alkyl, trifluoromethyl, trifluoroethyl, C (= O ^ H ₂ or C _1-3 alkylC (= O).

In one of the embodiments of the present invention, the ring formed between any of Κ _{ά 1} and K _a2 in the same Ό ₂ , two Ό ₂ , Cd and one Ό ₂ , or Cd and Ό ₃ , is selected from the group consisting of

- 2 032642

In one embodiment of the present invention, one of K ₂ is

and Κ _{1 is} selected from the group consisting of Η, B, C1, ΝΗ ₂ and OC1_ ₃ alkyl.

In one embodiment, one of Κ _{1-2 is} selected from the group consisting of

- 3 032642 and the other is selected from the group consisting of Η, P, C1, ΝΗ ₂ , methoxy, ethoxy and propoxy.

Another objective of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of

- 4 032642

- 5,032,642

- 6 032642

- 7 032642

- 8 032642

- 9 032642

- 10 032642

Brief Description of the Drawings

In FIG. 1-1 shows the results of a pharmacodynamic study of I ίη νίνο of the test drug in a model of a subcutaneous tumor xenograft of human colon cancer CO-04-0032, where:

1) the number of mice in each group was 5;

2) dosing volume: 10 μl / g depending on the body weight of the mice. If the loss of body weight exceeded 15%, then the dosage regimen should be adjusted accordingly;

3) solvent VKM120: 10% ΝΜΡ + 90% PEC300, PO, 00 x 5 weeks;

4) the solvent of compound 11: water, PO, 00 x 5 weeks.

In FIG. 1-2a, the results of a pharmacodynamic study of II ίη νίνο of the test drug are shown in a model of a subcutaneous tumor xenograft of human colon cancer CO-04-0032, where:

1) the number of mice in each group was 6;

2) dosing volume: 10 μl / g depending on the body weight of the mice. If the loss of body weight exceeded 15%, then the dosage regimen should be adjusted accordingly;

3) solvent VKM120: 10% ΝΜΡ + 90% PEC300, PO, 00 x 4 weeks;

4) the solvent of compound 11: water, PO, 00 x 4 weeks;

5) solvent of compounds 25, 27 and 32: 5% ΏΜ8ΏΜ + 60% PEC400 + 35% water.

In FIG. 1-2b shows the results of a pharmacodynamic study of II ίη νίνο of the test drug in a model of a subcutaneous tumor xenograft of human colon cancer CO-04-0032, where:

1) the number of mice in each group was 6;

2) dosing volume: 10 μl / g depending on the body weight of the mice. If the loss of body weight exceeded 15%, then the dosage regimen should be adjusted accordingly;

3) solvent VKM120: 10% ΝΜΡ + 90% PEC300, PO, 00 x 4 weeks;

4) the solvent of compound 11: water, PO, 00 x 4 weeks;

5) solvent of compounds 25, 27 and 32: 5% ΏΜ8ΏΜ + 60% PEC400 + 35% water.

In FIG. Figure 2-1 shows the results of a pharmacodynamic study of I ίη νίνο of the test drug in a mouse model of the subcutaneous tumor xenograft of human gastric cancer 8T-02-0013, where:

1) the number of mice in each group was 5;

2) dosing volume: 10 μl / g depending on the body weight of the mice. If the loss of body weight exceeded 15%, then the dosage regimen should be adjusted accordingly;

3) solvent VKM120: 10% NΜΡ + 90% RES300, PO, OO x 18 days;

4) the solvent of compound 11: water, PO, OO x 18 days;

5) the solvent of compound 15: 1% MS, PO, OO x 18 days.

In FIG. Figures 2-2 show the results of a pharmacodynamic study II ίη νίνο of the test drug in a mouse model of a subcutaneous tumor xenograft of human stomach cancer 8T-02-0013, where:

1) the number of mice in each group was 8;

2) dosing volume: 10 μl / g depending on the body weight of the mice. If the loss of body weight exceeded 15%, then the dosage regimen should be adjusted accordingly;

3) the solvent of compounds 25, 27 and 32: 5% ΏΜ8Θ + 60% RES400 + 35% water.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

can be replaced by or

- 11 032642

E is selected from the group consisting of C _1-6 alkyl and from 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, wherein said C _1-6 alkyl and from 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl are optionally substituted with 1, 2, or 3 K ₃ ; one of E and P is selected from the group consisting of -C (Ka1) (Ka2) -, -C (= ОЖК13) -, -Ν (Κ _ά 4) -, <(= N ^ 5) -, -8С = O ^ (M-, -8 (= Θ) Ν (Κ _ά7 ) -, -Ο-, -8-, -С (= О) О-, -С (= О) -, -С (= 8) -, -8 (= О) -, -8 (= О) ₂ - и ^ (Ка8) С (= О ^ (Ка9) -, and the other is selected from the group consisting of a single bond and -C (К _а1 ) (K _a2 ) -;

A and T are independently selected from the group consisting of N and C (K ₁ );

none or one of X, Υ and Ζ represents Ν, and the others represent C (K); B is selected from the group consisting of -CCCC) ^) -, -C (= ОЖ) -, -Ν ^) -, <(= N ^ 5) -, -8 (= О ^ (Cab) -, -8 (= O ^ (Ka7>, -O-, -8-, -С (= О) О-, -С (= О) -, -С (= 8) -, -8 (= О) -, - 8 (= ОД- и ^ (Ка9) С (= О ^ (Ка9) -;

the heteroatom or group of heteroatoms is each independently selected from the group consisting of -C (= O #), -Ν (Κ04) -, -Ο ^ ΝΚ ^) -, -8 (= О ^ (Cab) -, -8 (= O ^ (Ka7) -, -O-, -8-, -С (= О) О-, -С (= О) -, -С (= 8) -, -8 (= О) -, -8 (= 0) 2- and ^ (Ka8) C (= OGKa9) -;

t _{1 is} independently 0, 1, 2 or 3;

one of K _1-3 is

and others are selected from the group consisting of Η, E, C1, Br, I, ϋΝ, OH, 8Η, ΝΗ ₂ , CHO, COOH, C _1-10 alkyl or heteroalkyl, from 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, C _1-10 alkyl or heteroalkyl substituted with 3- to 10-membered cyclohydrocarbyl or heterocyclohydrocarbyl, 3- to 10-membered cyclohydrocarbyl-O- or heterocyclohydrocarbyl-O- and 3- to 10-membered cyclohydrocarbyl-amino-heterocyclo -, wherein said C _1-10 alkyl or heteroalkyl, 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, C _1-10 alkyl, and Whether heteroalkyl, substituted by 3do 10-membered tsiklogidrokarbilom or geterotsiklogidrokarbilom from 3do 10-membered tsiklogidrokarbil geterotsiklogidrokarbil-O- or -O- and from 3do 10-membered tsiklogidrokarbilamino- geterotsiklogidrokarbilamino- or optionally substituted K _0-1;

Ό _{1 is} selected from the group consisting of a single bond, -C (K _a1 ) (K _a2 ) -, -С (= О ^ (К _a3 ) -, -Ν (Κ4 ₄ ) -, -С (= КК _a 5 ) -, -8 (= О) Ж) -, -8 (= ОЖ) -, -О-, -8-, -С (= О) О-, -С (= О) -, -С (= 8) -, -8 (= О) -, -8 (= ОД- and ^ (Ка8) С (= ОЖКа9) -;

Ό ₂ represents —C (K _a1 ) (K _a2 ) -;

Ό _{3 is} selected from the group consisting of -Ν (Κ ₄ ) -, -С (= О ^ (К _а4 ) -, -№ (К _а4 ) С (= О) -, -№ (К _а4 ) С (= О) О-, ^ (К _а 4) ОС (= О) -, - ЖК ^ С ^ ОЖКи) -, -8 (= О) -, -8 (= О) ₂ -, -8 (= О) ^ (Kab) - and -8 (= ОЖ) -;

Cd is selected from the group consisting of Η, C _1-10 alkyl or heteroalkyl, from 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl and C _1-10 alkyl or heteroalkyl substituted by 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, wherein said C _{1 -10} alkyl or heteroalkyl, 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, and C _1-10 alkyl or heteroalkyl substituted with 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl are optionally substituted with K ₀₁ ;

η is 1, 2, 3, 4, 5, or 6;

optionally, any two K ₁ , K _a1 and K _a2 in the same Ό ₂ , two Ό ₂ , Cd and one Ό ₂ , or Cd and Ό _{3 are} attached together to the same carbon atom or hetero atom to form one or two 3-, 4-, 5- or 6-membered carbocyclic rings or heterocyclic rings;

_{KK a1} and K12 are independently selected from the group consisting of Η, E, C1, Br, I, С№, О11, 8Η, ΝΗ ₂ , СΗΟ, СООЦ С (= О ^^, 8 (= О ^^, 8 (= O) ^^, C _1-10 alkyl or heteroalkyl, 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, and C _1-10 alkyl or heteroalkyl substituted with 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, wherein said C _1-10 alkyl or heteroalkyl, 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, and C _1-10 alkyl or heteroalkyl substituted with 3 to 10 membered cyclohydrocarbyl or heterocyclohydrocarbyl, optionally substituted hens K01;

K _{01 is} selected from the group consisting of E, C1, Br, I, С№, О11, 8Η, ΝΗ ₂ , СΗΟ, СΟΟΗ and К ₀₂ ;

K _{02 is} selected from the group consisting of C _1-10 alkyl, C _1-10 alkylamino, Ν, Ν-di (C _1-10 alkyl) amino, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkoxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkoxycarbonyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkylsulfinyl, 5 to 6 membered unsaturated heterocyclyl and 6 to 12 membered aryl or heteroaryl;

a heteroatom or a group of heteroatoms each is independently selected from the group consisting of ) -, -О-, -8-, = О, = 8, -С (= О) О-, -С (= О) -, -С (= 8) -, -8 (= О) -, -8 (= 0) 2- and ^ (К _а 8) С (= ОЖК _a 9) -;

- 12 032642

Κ ^ _3- ά9 is independently selected from the group consisting of H, OH, ΝΗ _2, and B ₀₂ ;

B _{02 is} optionally substituted with B ₀₀₁ ;

Κοοι is selected from the group consisting of G, C1, Br, I, ΟΝ, OH, CHF ΝΗ (ΟΗ3), ΝΙΕ, CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, methyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl and methylsulfinyl;

in any of the above cases, the amount of each of B ₀₁ or B _{001 is} independently 0, 1, 2, or 3, and the number of each heteroatoms or groups of heteroatoms is independently 1, 2, or 3.

In one embodiment, the aforementioned E is selected from the group consisting of C _1-6 alkyl and C _3-6 cycloalkyl, wherein said C _1-6 alkyl and C _3-6 cycloalkyl are substituted with B ₃ and the amount of B ₃ is 0 , 1, 2 or 3, or E is selected from the group consisting of

θ2Τ> ^ 19 where none, or one, or two, or three O ₁ ~ ₅ represent Ν, and the others represent C (Ke);

O _{6 is} selected from the group consisting of -C (B ₃ ) (B ₃ ) -, -C (= O ^ (B _3a ) -, -Ν (Β _3α ) -, ^ (= ΝΒ _3α ) -, -8 (()) _: \ (1 < _3а ) -, -8 (= ^ (^) -, -О-, -8-, -С (= О) О-, -С (= О) -, -С (= 8) -, -8 (= О) -, -8 (= О) ₂ - and -Ν ^ Μ ^ Ν ^) -;

none, or one, or two O _7-9 are Ν, and the others are C (B ₃ );

none, or one, or two, or three, or four O ₁₀ ~ ₁₆ represent Ν, and the others represent C (B ₃ );

O _{17 is} selected from the group consisting of Ν and C (B ₃ );

not one, or one, or two, or three O ₁₈ ~ ₂₂ are selected from the group consisting of -C ^ O ^ B ^) -, -Ν (Β _3α ) -, -С ^^ a) -, -З ^ ОЬХКеа ) -, -δ ^ Ν ^) -, -О-, -8-, -С (= О) О-, -С (= О) -, -С (= 8) -, -8 (= О) -, -8 (= О) ₂ - and -ХКз ^^ О ^ Кза) -, and others are -С (В ₃ ) (В ₃ ) -;

_{3a is} selected from the group consisting of C _1-10 alkyl, C _1-10 alkylacyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _1-10 alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylacyl, C _3-10 cycloalkoxycarbonyl, C _3-10 cycloalkylsulfonyl, C _3-10 cycloalkylsulfinyl, 5 to 6 membered unsaturated heterocyclyl and 6 to 10 membered aryl or heteroaryl.

In one embodiment of the present invention, the above E is selected from the group

In one embodiment, the aforementioned E is selected from the group consisting of

and C _1-3 alkyl, all of which are optionally substituted with 1, 2 or 3 halogens, OH, OC _1-3 alkyl,

- 13 032642

ΟΝ, ΝΗ _2, MH (C1 _-3 alkyl) ^ C _1-3 alkyl) _2, C _1-3 alkyl, trifluoromethyl, trifluoroethyl, Ο (= Θ) ΝΗ _2, C1 _-3 alkylC (= O) C _1-3 alkylС (= О ^ Н, С _1-3 alkyl 8 (= О), С _1-3 alkyl 8 (= Ο) ΝΗ, С _1-3 alkyl 8 (= О) ₂ or С1-closed 8 ( = O) 2KN.

In one embodiment, the aforementioned E is selected from the group consisting of

In one embodiment of the present invention, one of the aforementioned b and P is selected from the group consisting of -8 (= Ο) ₂ ΝΗ-, -8 (= Ο) ₂ -, -ΝΗ- and -Ν№ (= Θ) ΝΗ -, and the other is selected from the group consisting of a single bond and -C11 ₂ -.

In one embodiment of the present invention, none or one of the above X, Υ, and Ζ is Ν, and the others are selected from the group consisting of C ^ C (C11 ₃ ), C (CE ₃ ), CC1, and CE.

In one embodiment, the aforementioned A and T are independently selected from the group consisting of Ν, SI, C (C ^), C (CE ₃ ), CC1 and CE; alternatively, B is selected from the group consisting of ΝΗ, Ν ^ Η ₃ ) and ^ CE ₃ ).

- 14 032642

In one embodiment of the present invention, the aforementioned ring formed between any two Κι, K ^ and K ^ in the same Ώ ₂ , two Ώ ₂ , K4 and one Ώ ₂ , or K ₄ and Ό ₃ , is selected from the group consisting of

'Ό Ό- ^{/ Ν} Ο Ν · χθ

all of which are optionally substituted with 1, 2 or 3 halogens, OH, OC1 _-3 alkyl, ΟΝ, ΝΗ ₂ , ΝΗ (Ομ ₃ alkyl), ^ C _1-3 alkyl) ₂ , C _1-3 alkyl, trifluoromethyl, trifluoroethyl, 0 (= Ο) ΝΗ ₂ , C _1-3 alkylC (= O), C _1-3 alkylC (= O) MH, C _1-3 alkyl 8 (= O), C _1-3 alkyl 8 (= Ο) ΝΗ, C _1-3 alkyl 8 (= O) ₂ or C _1-3 alkyl 8 (= O) ^ H.

In one embodiment of the present invention, the aforementioned ring formed between any two K ₁ , K _b1 and K _b2 in the same Ό ₂ , two Ό ₂ , K ₄ and one Ό ₂ , or K ₄ and Ό ₃ , is selected from a group consisting of

In one embodiment of the present invention, one of the above K _1-3 is

and others are selected from the group consisting of Η, E, C1, Br, I, SI OH, 8H, ΝΗ ₂ , CHO, COOH, OK _a , Ν (Κβ) (Κ _€ ), C _1-3 alkyl and cyclopropyl, wherein said C _1-3 alkyl and cyclopropyl are optionally substituted with Kb;

Ό _{1 is} selected from the group consisting of a single bond, -C (Ke) (Ke) -, -С (= О ^ (К _а ) -, -Ν (Κ _α ) -, -С (= КК _а ) -, -8 (= ОА (Ка) -, -8 (= ОЯ (К) -, -О-, -8-, -С (= О) О-, -С (= О) -, -С (= 8 ) -, -8 (= О) -, -8 (= О) ₂ - and -МКа) С (= О) МКа) -;

1) ₂ represents —C (K _a ) (Ka) -;

η is 1, 2, 3, 4, 5, or 6;

K _a , K _b and K are independently selected from the group consisting of H, C _1-6 alkyl and C _3-6 cycloalkyl, where indicated

- 15 032642 C _1-6 alkyl and C _3-6 cycloalkyl are optionally substituted with K ^;

K _{e is} selected from the group consisting of Η, C _1-6 alkyl or alkoxy, and C _3-6 cycloalkyl or cycloalkoxy, wherein said C _1-6 alkyl or alkoxy and said C _3-6 cycloalkyl or cycloalkoxy are optionally substituted with K ^;

Ka is selected from the group consisting of P, C1, Br, I, SI OH, CHO, COOH, CH ₃ , CP ₃ , CH ₃ O and CH ₃ CH ₂ O, and the amount of K is 0, 1, 2 or 3;

Optionally, any two of K _1, K _and Ca and at the same Ό _2, two Ό _2, K or _a and one Ό ₂ are attached together to the same carbon atom or oxygen atom to form a 3- or two, A 4-, 5- or 6-membered carbocyclic ring or an oxacyclic ring in which the number of oxygen atoms is 1 or 2.

In one embodiment of the present invention, the aforementioned ring formed between any two K ₁ , K _a and K _a in the same Ό ₂ , two Ό ₂ , or K _a and one Ό ₂ , is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl and 1,3 dioxolanyl.

In one of the embodiments of the present invention, one of the above K _1-3 selected from the group consisting of

- 16 032642 and others selected from the group consisting of Η, P, C1, Br, I, ΟΝ, OH, ΝΗ ₂ , methyl, ethyl, propyl, methoxy, ethoxy, propoxymethylamino, dimethylamino, halomethyl, haloethyl, halopropyl, aminomethyl, aminoethyl, aminopropyl and cyclopropyl.

In one embodiment of the present invention, the aforementioned compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds 1 to 25 and compounds 27 to 99.

Definitions Used

Unless otherwise specified, the following terms and phrases in the context of this document are intended to mean the following meanings. A specific term or phrase without a specific definition should not be considered vague or unclear, but should be understood in their generally accepted meaning. When a trade name is used in this description, it is intended to mean the corresponding product or its active ingredient.

C _1-10 selected from the group consisting of C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ ;

The devil is selected from the group consisting of C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ .

C _1-10 alkyl or heteroalkyl, C _3-10 cyclohydrocarbyl or heterocyclohydrocarbyl, and C _1-10 alkyl or heteroalkyl, wherein said C _1-10 alkyl or heteroalkyl is substituted with C _3-10 cyclohydrocarbyl or heterocyclohydrocarbyl, include, but are not limited to:

C _1-10 alkyl, C _1-10 alkylamino, H #di (C _1-10 alkyl) amino, C _1-10 alkoxy, C _1-10 alkanoyl, C _1-10 alkoxycarbonyl, C _1-10 alkylsulfonyl, C _{1 -10} alkylsulfinyl, C _3-10 cycloalkyl, C _3-10 cycloalkylamino, C _3-10 heterocycloalkylamino, C _3-10 cycloalkoxy, C _3-10 cycloalkylacyl, C _3-10 cycloalkyloxycarbonyl, C _3-10 cycloalkylsulfonyl and C _3-10 cycloalkylsulfinyl;

methyl, ethyl, n-propyl, isopropyl, -CH ₂ C (CH ₃ ) (CH ₃ ) (OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropionyl, benzyloxy, trifluoromethyl, aminomethyl, hydroxymethyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl, ethoxy, acetyl, ethylsulfonyl, ethoxycarbonyl, dimethylamino, diethylamino, dimethylaminocarbonyl and diethylaminocarbonyl;

MSC) 2, F (SS), -CH2SE3, -CH2CH2SE3, -CH2CH2E, -CH2CH28 (= O) 2CH3, -CH ₂ CH ₂ MF

-CH2CH (P) (CH3) 2, -CH2CH2E, -CH2SE3, -CH2CH2SE3,

-CH2CH (OH) (CH3) 2,

-CH ₂ CH ₂ MH ₂ ,

—CH ₂ CH ₂ OH, —CH ₂ CH ₂ OCH ₃ , —CH ₂ CH ₂ CH ₂ OCH ₃ , —CH ₂ CH ^ (CH3) ₂ , -8 (= O) ₂ CH ₃ , —CH ₂ CH ₂ 8 (= O) ₂ CH ₃ ,

- 17 032642

- 18 032642

phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2,3-azolyl, 1,2,3 triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 4H-pyranyl, pyridyl, piperidyl, 1,4-dioxanyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-trithyanil , 1,3,5-triazinyl, benzofuranyl, benzothiophenyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl and quinoxalinyl;

methyl, ethyl, propyl, methoxy, ethoxy, methylamino, dimethylamino, halomethyl, haloethyl, halopropyl, aminomethyl, aminoethyl, aminopropyl, cyclopropyl; and

- 19 032642

The term pharmaceutically acceptable, as used herein, refers to such compounds, materials, compositions and / or dosage forms, within the framework of an approved medical evaluation, which are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, at the same time with a reasonable benefit / risk ratio.

The term “pharmaceutically acceptable salt” refers to a salt of a compound of the present invention, which is prepared using a compound with specific substituents found in accordance with the present invention and a relatively non-toxic acid or base. When the compound of the present invention contains a relatively acidic functional group, a base addition salt can be prepared by reacting the compound in neutral form with a sufficient amount of the base in a pure solution or a suitable inert solvent. A pharmaceutically acceptable base addition salt includes sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts, or the like. When the compound of the present invention contains a relatively alkaline functional group, an acid addition salt can be obtained by reacting the compound in neutral form with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of a pharmaceutically acceptable acid addition salt include an inorganic acid salt, wherein the inorganic acid includes hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphoric acid and etc .; and an organic acid salt, wherein the organic acid includes such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, cork acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, phenyl sulfonic acid ptoluenesulfonic acid, citric acid, tartaric acid, methyl sulfonic acid and the like; and also includes an amino acid salt (e.g., arginine), and a salt of an organic acid such as glucuronic acid and the like (see Vegde e! a1., Ryagshasei 11ca1 8a11z, 1oigia1 oG Ryagshaseiisa1 8c1eise 66: 1-19 (1977)). Some specific compounds of the present invention contain alkaline and acid functional groups so as to be able to be converted to any base addition salt or acid addition salt.

Preferably, the neutral form of the compound is formed by contacting the salt with a base or acid in the usual manner, and then by separating the starting compound. The difference between the initial form of the compound and various forms of salts lies in some physical properties (for example, different solubilities in a polar solvent).

The term pharmaceutically acceptable salt, as used herein, refers to derivatives of a compound of the present invention, when the parent compound is modified by conversion to a salt with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to: an inorganic or organic acid salt of a base (such as an amine), an alkali metal or an organic acid salt (such as a carboxylic acid), and so on. A pharmaceutically acceptable salt includes typical non-toxic salts or quaternary amides.

- 20 032642 monium salts of the parent compound, such as a salt formed by a non-toxic inorganic or organic acid. Typical non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids, where inorganic acids or organic acids are selected from 2-acetoxybenzoic acid, 2-isethionic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate , carbonic acid, citric acid, ethylenediaminetetraacetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycol acid, hydrobromic acid, hydrochloric acid, hydriodate, hydroxyl, hydroxyl naphthalene, isethionic acid, lactic acid, lactose, dodecansulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamic acid, pantothene acid, phenylacetic acid, phosphoric acid, polygalacturonate, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, sulfonyls hydrochloric acid, sulfuric acid, tannic acid, tartaric acid and p-toluenesulfonic acid.

The pharmaceutically acceptable salt of the present invention can be synthesized using the starting compound containing an acidic or alkaline group, in the usual chemical way. Typically, a salt production process involves reacting these compounds in the form of free acids or bases with a stoichiometric amount of suitable bases or acids in water or an organic solvent, or in a mixture of water and an organic solvent. In general, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.

In addition to the salt form, there is a prodrug form of the compound of the present invention. A prodrug of a compound described in the present invention is readily converted to a compound of the present invention by chemical reactions under physiological conditions. In addition, the prodrug can be converted into a compound of the present invention by a chemical or biochemical method under ίη νίνο conditions.

Some compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated form is similar to the unsolvated form, both of which are included in the scope of the present invention. Some compounds of the present invention may exist in polycrystalline or amorphous forms. Some compounds of the present invention may contain asymmetric carbon atoms (optical center) or double bonds. Racemic isomers, diastereomers, geometric isomers and individual isomers are included in the scope of the present invention.

A schematic representation of the racemic, ambiscalemic and scalemic or enantiomerically pure compounds of the present invention is presented in Maig, ί. Siet. Fuck 1985, 62: 114120. Unless otherwise indicated, the absolute configuration of the stereo center is represented by a wedge-shaped bond and dotted bonds. When the compound of the present invention contains a vinyl double bond or other geometric asymmetric centers, unless otherwise indicated, the geometric isomers E and включены are included. Similarly, all tautomeric forms are included within the scope of the present invention.

The compound of the present invention may exist in the form of geometric or stereoisomeric isomers. The present invention contemplates all of these compounds, including cis and trans isomers, (-) and (+) enantiomers, (B) and (8) enantiomers, diastereomers, (O) isomers, (b) isomers, and also racemic mixtures and other mixtures, such as enantiomer or diastereoisomer enriched mixtures, all of these mixtures are included in the scope of the present invention. Other asymmetric carbon atoms may be present in substituents, such as alkyl. All of these isomers and mixtures thereof are included in the scope of the present invention.

Optically active (B) - and (8) -isomers and (Ό) - and (b) -isomers can be obtained using asymmetric synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is required, it can be obtained by asymmetric synthesis or derivatization with chiral auxiliary reagents, where the resulting diastereomeric mixtures are separated and the auxiliary groups are cleaved to obtain the desired pure enantiomer. Alternatively, when the molecule contains an alkaline functional group (such as amino) or an acid functional group (such as carboxylic), this molecule interacts with the corresponding optically active acid or base to form a diastereomeric salt, the diastereomer is separated by fractional crystallization or chromatography, which are known in the art, and then the pure enantiomers can be reused. In addition, the separation of enantiomers and diastereomers is usually carried out using a chromatographic method, and a chiral stationary phase is used in the chromatographic method, and optionally in combination with a chemical derivatization method (for example, carbamate is obtained from an amine).

The compound of the present invention may contain unnatural proportions of the atomic isotopes of one or more atoms forming the compound. For example, the compound may be labeled 21 032642 but with a radioactive isotope such as tritium ( ³ H), iodine-125 ( ¹²⁵ 1) or C-14 ( ¹⁴ C). All variants formed by isotopes of the compound disclosed in the present invention, whether they are radioactive or not, are included in the scope of the present invention.

The term pharmaceutically acceptable carrier refers to any composition or vehicle that is capable of transmitting an effective amount of the active substance described in the present invention, does not affect the biological activity of the active substance and does not have toxic side effects on the body or patient. Typical carriers include water, oil, plants and minerals, a cream base, ointment lotion forms, etc. These forms include suspensions, thickeners, transdermal penetration enhancers, etc. Their compositions are well known to those skilled in the cosmetic or local pharmaceutical field. For other information about the medium, please contact Veshshdkop: ТНе 8с1епсе апб Ртасйсе οί Ряатшасу, 2151 Еб., ИрршсоИ. \ UP1ίαιιΐ5 & \ U11ksh5 (2005), the contents of which are incorporated into this description by reference. The term excipient, as a rule, refers to a carrier, diluent and / or medium necessary to obtain an effective pharmaceutical composition. For a drug or pharmacologically active substance, the term effective amount or therapeutically effective amount refers to a sufficient amount of a drug or preparation that can achieve the desired effects, but is not toxic. With respect to the oral dosage form of the present invention, an effective amount of the active substance in the composition means the amount necessary to achieve the desired effects when the active substance is combined with another active substance in the composition.

The determination of the effective amount varies from person to person depending on the age and general condition of the subject, as well as on the specific active substance. A suitable effective amount in some cases can be determined by a person skilled in the art in accordance with generally accepted tests. The term active ingredient, therapeutic agent, active substance or active agent means a chemical compound that can effectively treat a target disorder, disease or condition.

The term substituted refers to one or more hydrogen atoms in a particular atom substituted with a substituent, including deuterium and hydrogen variants, as long as the valence state of a particular atom is normal and the compound obtained after substitution is stable. When the substituent is a ketone group (i.e., = 0), this means that two hydrogen atoms are substituted. Substitution of the ketone group does not occur in aryl. The term optionally substituted means that it can be substituted or not substituted, and, unless otherwise indicated, the type and number of substituents can be arbitrary, provided that this can be achieved in the field of chemistry.

When one of the variables is a simple connection, this means that the two groups with which the variable is associated are directly related to each other. For example, when b in A-b-Ζ represents a single bond, A-b-Ζ actually means that the structure is A-Ζ.

When any variable (e.g., B) occurs more than once in the composition or structure of a compound, the definition in each case is independent. Therefore, for example, if a group is substituted with 0-2 V, this group may be optionally substituted with no more than two B, and B in each case has an independent variant. In addition, a combination of substituents and / or their variants is allowed only if such a combination leads to a stable connection. For example, a structural unit or indicates that substitution can occur at any position in cyclohexyl or cyclohexadienyl.

When the substituent bonds can be bonded to two atoms of the ring, the substituent can be bonded to any atoms in the ring. When it is not specified through which atom the indicated substituent combines with a chemical structural formula, including a compound that is not specifically mentioned, this substituent can be bonded through any of its atoms. The combination of substituents and / or their variants is allowed only if this combination leads to a stable connection.

A substituent for an alkyl and heteroalkyl group (including groups that are typically alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) is generally referred to as an alkyl substituent that may be selected, but not limited to, from one or more of the following groups: -B ', -OV', = O, = ΝΒ ', = ΝОВ', -ЫВ'В, -8В ', halogen, -81В'ВВ', OS (О) В ', -С (О) В ', -СО ₂ В', -СЫВ'В, -ОС (О) ЫВ'В, -ВИВ (О) В ', MV'С (О) MVВ', -ВИВ (О) ₂ V ', -ΝΚ .....- С (MV'BB') = MV, NVB (NVB) = NV ', -8 (O) B', -8 (O) ₂ B ',

-8 (O) ₂ NV'B, NV8O ₂ B ', -CI, -O ₂ , -Ν ₃ , -CH (R) ₂ and fluorine (C ₁ -C ₄ ) alkyl, and the number of substituents is from 0 to (2sh '+ 1), where w' represents the total number of carbon atoms in the group. B ', B, B', B and B .....

each independently preferably is H, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (for example, aryl substituted with 1 to 3 halogen atoms) and substituted or unsubstituted alkyl, alkoxy, thioalkoxy or aralkyl. When a compound of the present invention includes more than one B group, for example, each of the B groups is independently selected as each of the B ′, B, B ′, B, and B ′ groups when more than one of these groups is included. When B 'and B at 22 032642 are connected to the same nitrogen atom, they together with the nitrogen atom can form a 5-, 6- or 7-membered ring. For example, -ΝΚ'Κ is intended to include, but not limited to, 1 pyrrolidinyl and 4-morpholinyl. In accordance with the above discussion of substituents, one of skill in the art can understand that the term alkyl is intended to include a group formed by the addition of a carbon atom to a non-hydrogen group such as haloalkyl (e.g., —CH ₃ , —CH ₂ CP ₃ ), and acyl (e.g., —C (O) CH ₃ , —C (O) CP ₃ , —C (O) CH ₂ OCH ₃ , etc.).

Like a substituent for an alkyl group, a substituent for an aryl and heteroaryl groups is generally referred to collectively as an aryl substituent, which may be selected from such as -K ', -OK', -ΝΚ'Κ, -8K ', -halogen, -8ίΚ'ΚΚ ', OS (O) K, -C (O) K, -CO ₂ K', -SOYK'K, -OS (O) YK'K, -К'Ό (Ο) Κ ', ΝΚΌ (Ο) ΝΚΚ ', -YKS (O) ₂ K', -ΝΚ .....- Ο (ΝΚ'ΚΚ ') = ΝΚ, ΝΚΟ (ΝΚ'Κ) = ΝΚ', -8 (O) K ' ,

-δ (Ο) ₂ Κ ', -8 (Ο) ₂ ΝΚ'Κ, ΝΚ8Ο ₂ Κ', -ΟΝ, -ΝΟ ₂ , -Ν ₃ , -CH (P11) ₂ , fluorine (С1-С ₄ ) alkoxy and fluoro _(C1-C4) alkyl, the number of the substituents is in the range from zero to the total number of open valences on the aromatic ring system; where K ¹ , K, K ¹ , K and K ..... are independently from each other and are preferably selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When the compound of the present invention includes more than one K group, for example, each of the K groups is independently selected, like each of the K ¹ , K, K ¹ , K and K ..... groups, when more than one of these groups included. Two substituents attached to adjacent atoms in the aryl or heteroaryl ring may optionally be substituted with a substituent with the general formula —T — C (O) - (CCK ′) d-i—, where T and are independently selected from the group consisting of - ΝΚ-, -0-, CCM'- and single bond, and with | represents an integer from 0 to 3. Alternatively, two substituents attached to adjacent atoms in the aryl or heteroaryl ring may optionally be substituted with a substituent with the general formula —A (CH ₂ ) gB—, where A and B are independently selected from the group consisting of -SCC'-, -Ο-, -ΝΚ-, -8-, -8 (0) -, δ (0) ₂ -, -8 (Ο) ₂ ΝΚ'- and a single bond, and represents an integer from 1 to 4. Optionally, a single bond in a new ring formed in this way can be replaced by a double bond. Alternatively, two substituents attached to adjacent atoms in the aryl or heteroaryl ring may optionally be substituted with a substituent of the general formula —A (CH ₂ ) gB—, where 8 and ά are each independently selected from an integer from 0 to 3, and X represents -0-, -ΝΚ ', -8-, -8 (0) -, -8 (О) ₂ - or -8 (Ο) ₂ ΝΚ'-. The substituents K, K ', K and K' are each independently preferably selected from the group consisting of hydrogen and substituted or unsubstituted _(C1-C6) alkyl.

Unless otherwise indicated, the term halo or halogen alone or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom. In addition, the term haloalkyl is intended to include monohaloalkyl and polyhaloalkyl. For example, the term halo _(C1-C4) alkyl is intended to include, but not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3brompropila, etc. Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. The term alkoxy means that the aforementioned alkyl group with a certain number of carbon atoms is connected to an oxygen bridge. S1_ ₆ alkoxy include C 1, C _2, C _3, C _4, C ₅ and C ₆ alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, mzo-propoxy, n-butoxy, va-butoxy, tert-butoxy, n-pentyloxy and 8pentyloxy. The term cycloalkyl includes saturated cycloalkyls such as cyclopropyl, cyclobutyl and cyclopentyl. From 3 to 7 membered cycloalkyl includes C ,. C ₄ , C5, Cb and C-cycloalkyl. The term alkenyl includes straight or branched hydrocarbon chains in which there are one or more C — C double bonds on any stable chain sites, such as vinyl and propenyl.

The term halo or halogen means fluoro, chloro, bromo and iodo. Unless otherwise specified, the term hetero means a heteroatom or heteroatom group (i.e., a group containing a heteroatom) including atoms other than carbon (C) and hydrogen (H) and groups containing these heteroatoms, for example, including oxygen (O), nitrogen (Ν), sulfur (8), silicon (81), germanium (be), aluminum (A1), boron (B), -0-, -8-, = 0, = 8, -С (= 0) 0 -, -С (= 0) -, -С (= 8) -, -8 (= 0), -8 (= О) ₂ - and optionally substituted -0 (= 0) Ν (Η) -, -Ν (Η) -, -C (= ON) -, -8 (= Ο) ₂ Ν (Η) - or -8 (= 0) Ν (Η) -.

Unless otherwise indicated, the term ring refers to substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. A ring includes one ring, a linked ring, a spiro ring, a fused ring or a bridging ring. The number of atoms in a ring is generally defined as the affinity of the ring, for example, a 5- to 7-membered ring is a closed ring with 5-7 atoms. Unless otherwise indicated, the ring optionally contains 1-3 heteroatoms. Thus, a 5- to 7-membered ring includes, for example, phenyl, pyridinyl and piperidinyl; on the other hand, the term 5- to 7-membered heterocycloalkyl includes pyridyl and piperidinyl, but does not include phenyl. The term ring also includes a ring system containing at least one ring, where each ring independently corresponds to the above definition.

Unless otherwise indicated, the term heterocycle or heterocyclyl refers to a stable monocyclic, bicyclic or tricyclic ring containing a heteroatom or a group of heteroatoms, they may be saturated, partially unsaturated or unsaturated (aromatic 23,032,642 mi), and they contain carbon atoms and 1, 2, 3 or 4 heteroatoms in the ring, which are independently selected from the group consisting of Ν, O and 8, where any of the aforementioned heterocycles can be condensed with a benzene ring to form a bicyclic ring. Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N0 and 8 (0) p). The nitrogen atom may be substituted or unsubstituted (i.e., N or ΝΚ, where B is H or other substituents as defined herein). The heterocycle can be attached to the side group of any heteroatoms or carbon atoms with the formation of a stable structure. If the resulting compound is stable, the heterocycle described herein may be substituted on its carbon or nitrogen atom. The nitrogen atom in the heterocycle is optionally quaternized. A preferred embodiment of the invention is such that the total number of 8 and O atoms in the heterocycle is more than 1 and these heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of 8 and O atoms in the heterocycle is not more than 1. As used herein, the term aromatic heterocyclic group or heteroaryl refers to a stable 5-, 6-, 7-membered monocyclic or bicyclic or 7-, 8-, 9 - or a 10-membered bicyclic heteroaromatic ring that contains carbon atoms and 1, 2, 3, or 4 heteroatoms in the ring, which are independently selected from the group consisting of Ν, O, and 8. The nitrogen atom may be substituted or unsubstituted (i.e., N or ΝΒ, where B represents H or other substituents as defined herein). The nitrogen and sulfur atoms may optionally be oxidized (i.e., N0 and 8 (0) p). It should be noted that the total number of 8 and O atoms in the heteroaromatic ring is not more than 1. Bridging rings are also included in the definition of a heterocycle. When one or more atoms (i.e., C, O, N or 8) are connected to two non-adjacent carbon atoms or nitrogen atoms, a bridging ring is formed. A preferred embodiment of the bridging ring includes, but is not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It should be noted that the bridge always converts a monocyclic ring into a tricyclic ring. In the bridging ring, the substituent in the ring may also be on the bridge.

Examples of heterocyclyl include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolinyl, benzenzo-azinazole, benzene-azinazole, benzenzo-azole, , decahydroxinolyl, 2H, 6H1,5,2-dithiazinyl, dihydrofuro [2,3-th] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indoalkenyl, indolinyl, indolysis l, indolyl, 3H-indolyl, isothino group, isobenzofuranyl, isoindolyl, isoindolinyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3,4-azadiazazylazole, 1,2,3azadiazazylazole , 5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, hydroxyindolyl, pyrimidyl, phenanthridinyl, phenanthroinyl, phenazine, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidyl, piperyl, piperidyl, piperyl, piperidyl, , pyranyl, pyrazinyl, pyrazolidinyl, pyrazoles silt, pyrazolyl, pyridazinyl, pyridoxazole, pyridimidazole, pyridothiazole, pyridyl, pyrrolidinyl, pyrrolynyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolisinyl, tetrahydrodinol tetrahydrodinol tetrahydrodinol tetrahydrodinol tetrahydrodinol 5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazyl, isothiazolylthienyl, thienoxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5triazolyl, 1,3,4-triazolyl and xanthenyl. Spirocyclic compounds and fused ring compounds are also included.

Unless otherwise specified, the term hydrocarbyl or its specific terms (such as alkyl, alkenyl, alkynyl, and phenyl) alone or as part of another substituent is a linear, branched or cyclic hydrocarbon group, or a combination thereof, which may be fully saturated or mono- or polyunsaturated, may be monosubstituted, disubstituted or multisubstituted, may include divalent or polyvalent atomic groups, and has a certain number of carbon atoms (for example, C1-Ciu represents from 1 to 10 atoms mov carbon). The term hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl and aromatic hydrocarbyl. Aliphatic hydrocarbyl includes linear and cyclic aliphatic hydrocarbyl, and specifically includes, but is not limited to, alkyl, alkenyl, and alkynyl. Aromatic hydrocarbyl includes, but is not limited to, 6 to 12 membered aromatic hydrocarbyl, such as phenyl, naphthyl, and the like. In some embodiments, the term alkyl denotes a linear or branched group of atoms or a combination thereof, which may be fully saturated, or mono- or polyunsaturated and may include divalent and polyvalent groups. Examples of saturated hydrocarbon groups include, but are not limited to, homologues or isomers of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, iso-butyl, cyclohexyl, (cyclohexyl) methyl , cyclopropylmethyl and n-amyl, n-hexyl, n-heptyl, n-octyl and the like. Unsaturated alkyl has one or more double bonds or triple bonds, and examples thereof include, but are not limited to: vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2

- 24 032642 butadienyl, 2,4-pentadienyl, 3- (1,4-pentadienyl), acetenyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers. Unless otherwise indicated, the term heterohydrocarbyl or its specific terms (such as heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl), alone or in combination with another term, means a stable linear, branched or cyclic hydrocarbon group or combination thereof, which consists of a certain number of atoms carbon and at least one heteroatom. In some embodiments, the term heteroalkyl, alone or in combination with another term, refers to a stable linear or branched hydrocarbon group or combination thereof, which consists of a certain number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatom is selected from the group consisting of B, O, N, and 8, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroatoms B, O, N, and 8 can be located at any internal positions of the heterohydrocarbyl (including the position in which the hydrocarbyl is attached to the rest of the molecule). Examples include, but are not limited to, —CH ₂ —CH ₂ —O — CH ₃ , —CH ₂ —CH ₂ —H — CH _; . -CH ₂ -CH ₂ - \ (CH _; ) -CH _; . -CH ₂ -8-CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -8 (O) -CH ₃ , -CH ₂ -CH ₂ -8 (O) ₂ -CH ₃ , -CH = CH-O -CH ₃ , -CH ₂ -CH = NOCH ₃ and -CH = CH- ^ CH ₃ ) -CH ₃ . No more than two heteroatoms may be adjacent, such as —CH ₂ —NH — OCH ₃ .

The terms alkoxy, alkylamino and alkylthio (or thioalkoxy) are idiomatic expressions that refer to alkyl groups attached to the rest of the molecule via an oxygen atom, an amino group or a sulfur atom, respectively.

Unless otherwise specified, the terms cyclohydrocarbyl, heterocyclohydrocarbyl, or specific terms thereof (e.g., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl and heterocycloalkynyl) are, independently or in combination with other terms, hydrocarbyl or hydrocarbyl. In addition, in terms of heterohydrocarbyl or heterocyclohydrocarbyl (e.g., heteroalkyl and heterocycloalkyl) heteroatoms may occupy a position in which the heterocyclic ring is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc. Non-limiting examples of heterocyclyl include 1- (1,2,5,6-tetrahydropyridinyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuranylindol-3-yl, tetrahydrothiophenidiophene 2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise specified, the term aryl means a polyunsaturated aromatic hydrocarbon substituent, which may be monosubstituted, disubstituted or multisubstituted. It can be monocyclic or polycyclic (preferably 1-3 rings). They are fused together or bonded covalently. The term heteroaryl refers to an aryl (or ring) containing from 1 to 4 heteroatoms. In an exemplary embodiment, the heteroatom is selected from the group consisting of B, Ν, O, and 8, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroaryl can be attached to the rest of the molecule via a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,

4-thiazolyl, 5-thiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl, 1-isoquinolyl,

5-isoquinolyl, 2-quinoxalyl, 5-quinoxalil, 3-quinolyl and 6-quinolyl. Substituents of any of the above aryl and heteroaryl ring systems are selected from acceptable substituents described below. For brevity, when used in combination with other terms (e.g., aryloxy, arylthio, aralkyl), aryl includes an aryl and heteroaryl ring as defined above. Thus, the term aralkyl is intended to include groups in which aryl is attached to alkyl (e.g., benzyl, phenethyl, pyridyl, methyl), including those alkyls where carbon atoms (e.g. methylene) have been replaced, for example, by oxygen atoms, such like phenoxymethyl, 2-pyridyloxymethyl, 3- (1naphthoxy) propyl.

The term substituted group refers to a functional group or atom, which can be replaced by another functional group or atom by means of a substitution reaction (for example, a nucleophilic substitution reaction). For example, typical displaceable groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzene sulfonate, p-tosylate; acyloxy such as acetoxy, trifluoroacetoxy, and so on.

The term protecting group includes, but is not limited to, amino protecting groups, hydroxyl protecting groups, and mercapto protecting groups. The term amino protecting groups denotes a protecting group that is suitable for preventing side reactions from interacting on the nitrogen atom of an amino group. A typical representative of the amino-protecting group includes, but is not limited to: formyl; acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); aryl methoxycarbonyl such as benzyloxycarbonyl (CX) and 9-fluorenylmethoxycarbonyl (Etoc); arylmethyl such as benzyl (Bp), triphenylmethyl (Tg), 1,1-bis- (4'-methoxyphenyl) methyl; silyl such as trimethylsilyl (TM8) and tert-butyldimethylsilyl

- 25,032,642 (TV8). The term hydroxyl protecting groups refers to a protecting group that is suitable for preventing adverse reactions of the hydroxyl group. A representative representative of the hydroxyl protecting group includes, but is not limited to: alkyl, such as methyl, ethyl, and tert-butyl; acyl such as alkanoyl (such as acetyl); arylmethyl such as benzyl (Bp), p-methoxybenzyl (PMB), 9fluorenylmethyl (Gt) and diphenylmethyl (ΌΡΜ); silyl such as trimethylsilyl (TM8) and tert-butyldimethylsilyl (TB8).

The compound of the present invention can be obtained using a variety of synthesis methods that are well known to a person skilled in the art, including the specific embodiments listed below, the embodiments obtained by combining specific embodiments with other chemical synthesis techniques and equivalent alternative methods that well known to the person skilled in the art. Preferred embodiments include, but are not limited to, examples of the present invention.

All solvents used in the present invention are commercially available and can be used without further purification. The reactions are usually carried out under an inert nitrogen atmosphere in an anhydrous solvent. The data of proton nuclear magnetic resonance were recorded on a Vgikeg Auapse III 400 spectrometer (400 MHz) with chemical shifts expressed in rhp towards tetramethylsilane. Mass spectra were measured on Adyep! 1200 8pez P1 from 6110 (& 1956A). The LC / MS or MS ΒΙιίιηηάζιι contains ΌΑϋ: 8ΡΌ-Μ20Α (LC) and the detector ΒΙιίιηηάζιι М1егота88 2020. The mass spectrometer is equipped with an electrospray ionization source (Ε8Ι) operating in positive or negative mode.

The following abbreviations are introduced in the present invention: ac is water; NATi is O- (7-azabenzotriazol-1-yl) -y, s, s', s'-tetramethyluronium hexafluorophosphate; GOS is Y- (3-dimethylaminopropyl) -Y'-ethylcarbodiimide hydrochloride; t-CPBA is 3chloroperbenzoic acid; eu | denotes an equivalent, equal in quantity; C1) 1 is carbonyldiimidazole; OSM is dichloromethane; PE is petroleum ether; ΌΙΑΌ represents diisopropylazodicarboxylate; ΌΜΓ is Ν, Ν-dimethylformamide; ΌΜ8Θ is dimethyl sulfoxide; EJAc is ethyl acetate; EUN is ethanol; ΟеΟН is methanol; ΓΈζ is benzyloxycarbonyl, which is an amino protecting group; Boc is tert-butoxycarbonyl, which is an amino protecting group; HOAc is acetic acid; NaCNBΓB is sodium cyanoborohydride; d.1. represents room temperature; O / Ν denotes overnight; TNG is tetrahydrofuran; Boc ₂ O is di-tert-butyl diarbonate; TGA is trifluoroacetic acid; ΌΙΡΕΑ represents diisopropylethylamine; VOSI is thionyl chloride; CB ₂ represents carbon disulfide; TUN is ptoluenesulfonic acid; ΝΓ8Ι represents No. fluoro-No.- (phenylsulfonyl) benzenesulfonamide; Ν ^ represents 1-chloropyrrolidin-2,5-dione; p-Vi ₄ KG is tetrabutylammonium fluoride; 1PgOH is 2-propanol; mp is the melting point.

The compounds are artificially named or named using the SIETO-GAGXK software, and the names of supplier catalogs are used for commercially available compounds.

Specific Embodiments

The following examples are provided to illustrate the present invention in more detail, but the scope of the present invention is not limited to this.

Scheme 1

Reaction conditions: a) tert-butyldimethylsilyl chloride, 1H-imidazole; B) 1-tert-butoxyΝ, Ν, Ν, Ν'-tetramethyldiaminomethane, heating; c) 2-amino-5-bromopyridine, acetic acid, heating; ά) acetic acid, microwaves; e) potassium carbonate, ΌΜΓ, heating; ί) K borate (boric acid),

- 26,032,642

1,1'-bis (diphenylphosphino) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating; d) methanesulfonyl chloride, triethylamine, dichloromethane, 0 ° C; I) D, D-difluoropiperidine, diisopropylethylamine, acetonitrile, heating.

Example 1. No. (5- (3- (2- (D, D-difluoro-1-piperidinyl) ethoxy) -D-oxopyrido [1,2-a] pyrimidin-7-yl] -2methoxypyridin-3-yl] -2, D-dimethylthiazole-5-sulfonamide

a) Ethyl 2 - ((tert-butyldimethylsilyl) oxy) acetate.

Ethyl glycolate (100 g, 961 mmol) and 1H-imidazole (130 g, 1.9 mol) were dissolved in dichloromethane (1 L) and placed in a three-necked round bottom flask, and tert-butyldimethylsilyl chloride (158 g, 1 mol) was added at 0 ° C. . The mixture was stirred at room temperature for 8 hours, washed with water (1 L x 3) and dried over sodium sulfate and concentrated to give the title compound (195 g, 93%) as a yellow oil.

'' And NMR (400 MHz, SES1E) ppm δ D.1D-D.09 (t, DN), 1.20-1.16 (ΐ, 3H), 0.83 (δ, 9H), 0.01 (δ, 6H).

b) (2) -ethyl 2 - ((tert-butyldimethylsilyl) oxy) -3- (dimethylamino) acrylate.

Ethyl 2 - ((tert-butyldimethylsilyl) oxy) acetate (96 g, 0. DD mol) and 1-tert-butoxy- ^ Н№, No. tetramethyldiaminomethane (91.9 g, 0.53 mol) were stirred under reflux for 2d h. The mixture was concentrated and the remaining liquid was purified by silica gel column chromatography to obtain the title compound (80 g, 66.6%) as a yellow oil.

¹ H NMR (D00 MHz, SOSU ррt δ 6.68 (δ, 1Н), D.13-D.11 (i, 2Н), 2.96 (δ, 6Н), 1.28-1.2Д ((, 3Н), 0.95 (δ 9H), 0.1D (δ, 6H).

c) (2) -ethyl 3 - ((5-bromopyridin-2-yl) amino) -2 - ((tert-butyldimethylsilyl) oxy) acrylate.

(2) Ethyl 3 - ((5-bromopyridin-2-yl) amino) -2 - ((tert-butyldimethylsilyl) oxy) acrylate (80 g, 293 mmol) and 2-amino-5-bromopyridine (50.6 g, 293 mmol) was dissolved in acetic acid (800 ml) and stirred at 80 ° C for 2 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (500 ml), washed with sodium carbonate solution (500 ml) and saturated brine (500 ml) ), dried over sodium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography to give the title compound (7D g, 63.0%) as a yellow oil.

¹ H NMR (D00 MHz, SES1 ₃ ) ppm δ 8.2D (δ, 1H), 7.75-7.72 (ά, 1H), 7.63-7.60 (4, 1H), 6.75-6.72 (ά, 1H), 6.57-6.5 D (ά, 1H), D.25-D.20 (i, 2H), 1.3D-1.30 ((, 3H), 1.02 (δ, 9H), 0.22 (δ, 6H).

ά) 7-Bromo-3-hydroxy-DN-pyrido [1,2-a] pyrimidin-D-one.

(2) -ethyl 3 - ((5-bromopyridin-2-yl) amino) -2 - ((tert-butyldimethylsilyl) oxy) acrylate (2 g x 34.169 mmol) was dissolved in acetic acid (13 ml x 3D) and stirred under microwave conditions at 1D0 ° C for D h. The mixture was concentrated and the residue was dissolved in ethanol (50 ml x 3D) and filtered to give the title compound (20.d g, 50%).

¹ H NMR (D00 MHz, C1.) C1.) Ppm δ 8.98 (δ, 1H), 8.1D (δ, 1H), 8.00-7.98 (ά, 1H), 7.79-7.77 (ά, 1H).

e) 7-Bromo-3- (2-hydroxyethyl) -DN-pyrido [1,2-a] pyrimidin-D-one.

2-Bromoethanol (933 mg, 7.D7 mmol), 7-bromo-3-hydroxy-DN-pyrido [1,2-a] pyrimidin-D-one (600 mg, 2.D9 mmol) and potassium carbonate (1.03 g, 7. Д7 mmol) was dissolved in Ν, Ν-dimethylformamide (10 ml), and the mixture was stirred at 110 ° С for 1 h in a protective atmosphere of nitrogen. LC / MS showed that the reaction is complete. The reaction solution was concentrated to obtain a crude product. The crude product was immediately used in the next step.

ί) No. (5- (3- (2-hydroxyethyl) -D-oxo-DN-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2, Dimethylthiazol-5 sulfonamide.

7-Bromo-3- (2-hydroxyethyl) -DN-pyrido [1,2-a] pyrimidin-D-one (70D mg, 2.D9 mmol) was dissolved in dioxane (10 ml) and water (2 ml), and No. (2-methoxy-5- (D, D, 5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyridin-3-yl) -2, d-dimethyl thiazole-5-sulfonamide (1.06) was added g, 2.d9 mmol), potassium carbonate (687 mg, d.97 mmol) and 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (50 mg). The reaction solution was stirred to cause a reaction at 100 ° C. for 3 hours. LC / MS indicated that the reaction was complete. The reaction solution was filtered and concentrated to obtain a crude product, and the crude product was purified using preparative high performance liquid chromatography to obtain the title compound (500 mg, d0%) as a white solid.

¹ H NMR (D00 MHz, SOSR pt δ 9.09 (δ, 1H), 8.2D (δ, 1H), 8.18 (ά, 1H), 8.01 (ά, 1H), 7.80-7.67 (t, 1H), D. 28-D.22 (t, 2H), D.01-3.92 (t, 5H), 2.65 (δ, 3H), 2.56 (δ, 3H).

d) 2 - ((7- (5- (2,4-Dimethylthiazol-2, D-dimethylthiazole-5-sulfonamido) -6-methoxypyridin-3-yl) -D

- 27 032642 oxo-4H-pyrido [1,2-a] pyrimidin-3-yl) oxy) ethyl methanesulfonate.

K- (5- (3- (2-Hydroxyethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) -2,4dimethylthiazole-5-sulfonamide (50.00 mg, 99.30 μmol) and triethylamine (20.10 mg, 198.60 μmol) were dissolved in dichloromethane, and methanesulfonyl chloride (13.65 mg, 119.16 μmol) was added to it at 0 ° C. The mixture was stirred to start the reaction at 0 ° C. for 1 h. TEC showed that the reaction was complete, and then dichloromethane (10 ml) and water (8 ml) were added to the reaction solution. The organic phase was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product was purified by silica gel column chromatography to give the title compound (55 mg, 95.2%) as a pale yellow solid.

¹ H NMR (400 MHz, COC1 ₃ ) ppm 9.08 (b, 1 = 1.10 Hz, 1H), 8.54 (b, 1 = 2.43 Hz, 1H), 8.21 ( _δ , 1H), 7.67-7.79 (t, 3H) 4.58-4.66 (t, 2H), 4.43-4.50 (t, 2H), 4.01 (δ, 3H), 3.17 (δ, 3H), 2.74 (δ, 3H), 2.46 (δ, 3H).

g) Y- (5- (3- (2- (4,4-difluoro-1-piperidinyl) ethoxy) -4-oxo-pyrido [1,2-a] pyrimidin-7-yl] -2-methoxypyridine- 3-yl] -2,4-dimethylthiazol-5-sulfonamide.

2 - ((7- (5- (2,4-Dimethylthiazol-2,4-dimethylthiazole-5-sulfonamido) -6-methoxypyridin-3-yl) -4-oxo4H-pyrido [1,2-a] pyrimidine- 3-yl) oxy) ethyl methanesulfonate (50.00 mg, 85.96 μmol) and 4,4-difluoropiperidine (12.50 mg, 103.16 μmol) were dissolved in acetonitrile (2 ml), and diisopropylethylamine (22.22 mg, 171.93 μmol) was added to the solution. The mixture was stirred to start the reaction at 50 ° C for 12 hours. Liquid chromatography-mass spectrometry showed that the reaction was completed. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified using preparative high performance liquid chromatography to give the title compound (15.00 mg, 28.77%) as a pale yellow solid.

¹ H NMR (400 MHz, CB ₃ OV) ppm 9.11 (b, 1 = 1.51 Hz, 1H), 8.30 (b, 1 = 2.26 Hz, 1H), 8.27 (δ, 1 H), 8.018.11 (t, 2H), 7.74 (b, 1 = 9.29 Hz, 1H), 4.35 (ΐ, 1 = 5.40 Hz, 2 H), 3.89 (δ, 3H), 2.94-2.97 (t, 2H), 2.78 (b, 1 = 5.02 Hz, 4 n), 2.64 (S, 3H), 2.49 (δ, 3H), 1.98-2.05 (t, 4H).

The following 5 compounds were also synthesized in accordance with the method of obtaining compound 1.

- 28 032642

Reaction conditions: a) 2-morpholinoethanol, dibromotriphenylphosphine, dichloromethane; B) 7-bromo-3-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one, potassium carbonate, Ν, Ν-dimethylformamide; c) 2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine) -3-amine, 1,1'-bis (diphenylphosphino) ferrocene palladium chloride potassium carbonate, dioxane, water, heating; ά) K-sulfonyl chloride, pyridine.

Example 7. 2,4-Dimethyl-No. (2-methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-4-one-7-yl) pyridin-3-yl) benzenesulfonamide

Soshrosh1s1

a) 4- (2-Bromoethyl) morpholine hydrobromide.

To a solution of 2-morpholinoethanol (4 g, 30.49 mmol) in dichloromethane (80 ml) was added portionwise dibromotriphenylphosphine (15.45 g, 36.59 mmol) at 0 ° C in a protective atmosphere of nitrogen. The mixture was stirred at 15 ° C for 18 hours. After completion of the reaction, the reaction solution was filtered, and the filter cake was washed with dichloromethane and dried under reduced pressure to obtain an almost white solid (5.1 g, 60.8%).

¹ H NMR (400 MHz, COC13) ppm δ 4.06 (ά, 1 = 12.2 Hz, 2H), 3.89-3.75 (t, 4H), 3.71-3.63 (t, 2H), 3.56 (ά, 1 = 12.5 Hz, 2H), 3.28-3.18 (t, 2H).

b) 7-Bromo-3- (2-morpholinoethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one.

In a protective atmosphere of nitrogen, 7-bromo-3-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one (1 g, 4.15 mmol), 4- (2-bromoethyl) morpholine hydrobromide (1.14 g, 4.15 mmol ) and potassium carbonate (1.72 g, 12.45 mmol) were added to Ν, Ν-dimethylformamide (80 ml), and the mixture was stirred at 120 ° C for 2 h. After completion of the reaction, the reaction solution was concentrated to remove Ν, Ν-dimethylformamide. Dichloromethane was added to the concentrated solution, and the resulting mixture was filtered. The filtrate was concentrated to give a brown solid (1.3 g, 88.4%).

¹ H NMR (400 MHz SSC) ppm δ 9.03 (ά, 1 = 1.7 Hz, 1H), 8.07 (8, 1H), 7.51 (άά, 1 = 2.2, 9.5 Hz, 1H), 7.457.29 (t, 1H ), 4.24 (I, 1 = 5.7 Hz, 2Н), 3.75-3.56 (t, 4Н), 2.78 (ί, 1 = 5.6 Hz, 2Н), 2.62-2.47 (t, 4Н).

c) 7- (5-amino-6-methoxypyridin-3-yl) -3- (2-morpholinoethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one.

In a protective atmosphere of nitrogen to a mixture of a solution of 7-bromo-3- (2-morpholinoethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one (100 mg, 0.28 mmol), 2-methoxy-5- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine) -3-amine (46 mg, 0.31 mmol) and potassium carbonate (117 mg, 0.85 mmol) in dioxane (5 ml) 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (8 mg, 0.008 mmol) and water (1 ml) were added. The mixture was stirred at 90 ° C. for 18 hours under a nitrogen blanket. After completion of the reaction, the reaction solution was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and then concentrated. The resulting crude product was purified using preparative thin layer chromatography and preparative liquid chromatography to obtain an almost white solid (23.82 mg, 22.06%).

¹ H NMR (400 MHz, SBS13) ppm δ 9.13 (ά, 1 = 1.5 Hz, 1H), 8.46 (ά, 1 = 2.5 Hz, 1H), 8.19 (8, 1H), 7.86 (άά, 1 = 2.5, 8.5 Hz, 1H), 7.79 (άά, 1 = 2.0, 9.0 Hz, 1H), 7.72-7.64 (t, 1H), 6.89 (ά, 1 = 8.5 Hz, 1H), 4.33 (ί, 1 = 5.5 Hz, 2H), 4.01 (8, 3H), 3.82-3.66 (t, 4H), 2.87 (S, 1 = 5.8 Hz, 2H), 2.62 (L8, 4H).

ά) 2,4-Dimethyl-No. (2-methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-4-one-7yl) pyridin-3 -yl) benzenesulfonamide.

To a solution of 7- (5-amino-6-methoxypyridin-3-yl) -3- (2-morpholinoethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one (100.00 mg, 251.62 μmol) in pyridine (3 ml) was added dropwise 2-methyl-4-fluorobenzenesulfonyl chloride (61.8 mg, 301.94 μmol). The reaction solution was stirred at 18 ° C for 18 hours. After completion of the reaction, pyridine was distilled off under reduced pressure. The residue was dissolved in dichloromethane and washed with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain a crude product. The crude product was purified using preparative liquid chromatography to give a yellow solid (23.16 mg, 16.11%).

¹ H NMR (400 MHz, СОС13) ppm δ 8.97 (8, 1Н), 8.16 (8, 1Н), 8.03 (ά, 1 = 2.2 Hz, 1Н), 7.91 (ά, 1 = 8.1 Hz, 1Н), 7.82 (ά, 1 = 2.0 Hz, 1Н), 7.65 (ά, 1 = 1.0 Hz, 2Н), 7.16 (ά, 1 = 8.1 Hz, 1Н), 7.10 (8, 1Н), 4.31 (ί, 1 = 5.6 Hz , 2H),

- 29 032642

3.99 (δ, 3Н), 3.82-3.66 (t, 4Н), 2.86 (ΐ, 1 = 5.6 Hz, 2Н), 2.64 ( _δ , 3Н), 2.61 (ά, 1 = 4.2 Hz, 4Н), 2.33 ( _δ , 3H). The following 13 compounds were also synthesized in accordance with the method of obtaining compound 7.

- 30,032,642

Reaction conditions: a) methanesulfonyl chloride, triethylamine, dichloromethane; B) potassium carbonate, Ν, Ν-dimethylformamide; c) No. (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin3-yl) -2,4-dimethylthiazole-5-sulfonamide, palladium, potassium carbonate, dioxane, water, heating.

Example 21. Ν- (2-Methoxy-5- (4-oxo-3 - (2- (2-oxopyrrolidin-1-yl) ethoxy) -4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) -2,4-dimethylthiazol-5-sulfonamide

a) 2- (2-Oxopyrrolidin-1-yl) ethyl methanesulfonate.

To a solution of 1- (2-hydroxyethyl) pyrrolidin-2-one (500.00 mg, 3.87 mmol) and triethylamine (1.17 g, 11.61 mmol) in dichloromethane (5 ml) was added methanesulfonyl chloride (531.97 mg, 4.64 mmol) at 0 ° C. The reaction solution was stirred at 0 ° C. for 1 h. After completion of the reaction, the reaction solution was washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and then concentrated to obtain a crude product (470.00 mg, 58.60%) as a yellow oil.

'11 NMR (400 MHz, CHC1 _; ) δ4.35 (I, 1 = 5.1 Hz, 2Η), 3.62 (I, 1 = 5.1 Hz, 2Η), 3.51 (I, 1 = 7.1 Hz, 2Η), 3.03 ( 8, 3Η), 2.40 (I, 1 = 8.1 Hz, 2Η), 2.06 (ds, 1 = 7.6 Hz, 2Η).

b) 7-Bromo-3- (2- (2-oxopyrrolidin-1-yl) ethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one.

A mixture of a solution of 7-bromo-3-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one (100.00 mg, 414.87 μmol), 2- (2-oxopyrrolidin-1-yl) ethyl methanesulfonate (257.94 mg, 1.24 mmol) and potassium carbonate (229.36 mg, 1.66 mmol) in Ν, Ν-dimethylformamide (10 ml) was stirred at 120 ° С for 18 h in a protective atmosphere

- 31,032,642 nitrogen sphere. After completion of the reaction, the reaction solution was concentrated. The concentrate was purified by silica gel column chromatography to obtain the product (210.00 mg, 79.05%, purity: 55%) as a yellow oil.

¹ H NMR (400 MHz, CBC1 ₃ ) δ 9.02 (ά, 1 = 1.7 Hz, 1H), 8.03 (δ, 1H), 7.51 (άά, 1 = 2.1, 9.4 Hz, 1H), 7.44-7.37 (t, 1Н), 4.23 (ΐ, 1 = 5.1 Hz, 2Н), 3.67 (δ, 2Н), 3.62 (ΐ, 1 = 7.0 Hz, 2Н), 2.34 (ΐ, 1 = 8.0 Hz, 2Н), 2.10-1.86 ( t, 2H).

c) Y- (2-Methoxy-5- (4-oxo-3- (2- (2-oxopyrrolidin-1-yl) ethoxy) -4H-pyrido [1,2-a] pyrimidin-7-yl) pyridine -3-yl) -2,4-dimethylthiazol-5-sulfonamide.

In a protective atmosphere of nitrogen to a mixture of a solution of 7-bromo-3- (2- (2-oxo-pyrrolidin-1-yl) ethoxy) -4Npyrido [1,2-a] pyrimidin-4-one (210.00 mg, 327.96 μmol), - (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) pyridin-3-yl) -2,4-dimethylthiazole-5-sulfonamide (145.19 mg, 327.96 μmol) and potassium carbonate (135.98 mg, 983.87 μmol) in dioxane (5 ml) were added 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (2.40 mg, 3.28 μmol) and water (1 ml). The mixture was stirred at 90 ° C. for 18 hours under a nitrogen blanket. After completion of the reaction, the reaction solution was concentrated. The concentrated residue was purified by preparative thin layer chromatography to give the title compound (60.07 mg, 30.41%) as a yellow solid.

¹ H NMR (400 MHz, SECC) δ 8.98 (δ, 1H), 8.20-8.06 (t, 3H), 7.92 (ά, 1 = 2.2 Hz, 1H), 7.68 (ά, 1 = 1.1 Hz, 2H), 7.58 (δ, 1H), 7.28 (ά, 1 = 2.4 Hz, 1H), 7.20-7.09 (t, 1H), 4.32 (ΐ, 1 = 5.1 Hz, 2H), 4.00 (δ, 3H), 3.84-3.65 (t, 4H), 2.42 (ΐ, 1 = 8.0 Hz, 2H), 2.08 (rms, 1 = 7.6 Hz, 2H).

The following 15 compounds were also synthesized in accordance with the method of obtaining compound 21. _______________________________________________________________________

Compound Structure M8 (E8) [M + H] ⁺ 22 1 O., Ν. Α Ί1 ^{0 0 n} % P 562 23 1 O = A. V *> 1 o o ο = έ = ο CAA ^N L R 598 24 + ++ o A ° o = [= o DAC Ό R 604 25 , 0 = A. V ⁰ ° T ° _{C |} ¹ P 548

- 32 032642

27 / 0 .. IX ΊΓ ⁰ Η Ν Ν _ν 0 = 3 = 0 Ρ C / φ- Ε 574 28 X _Ν. ΤΙ Π Γ ' Η Ν Ν ° = s = ° yd Ε 560 29th - ^ο γΊ? / x ° + °% Ε 560 thirty .0. >'> 0 NG ΧγΠΐ ιΓ' + ί '0 = 3 = 0 THEIR / + ^ΝΗ Α Ε 532 31 .0. .Ν. > ι 0 ι 11 ι ο Ε ^νη ? οΧο HHD Φ Ε 548 32 ^ 0 Ν θ d χτ ϊ ιΓ ^ο ™ ₂ 0 = 3 = 0 ΧΑ ^ ² Φ Ε 546

- 33,032,642

33 o4 = o ^N h 543 34 ⁰ η 0 = 8 = 0 'h 557 35 Χλ, Ν. '> 0 = 2 = °' ^{Ν =} ^ \ 531 36 n Ν _{Ν Ν} / ° 4 = ° BAA ¹ 516

Reaction conditions: a) 1,2-dibromoethane, potassium carbonate, ΏΜΕ, heating; B) 2,4-difluoro- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide, 1,1 ' bis (diphenylphosphino) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating; c) 1 Npyrazole, cesium carbonate, acetonitrile, heating.

Example 37. 2,4-Difluoro-L- (2-methoxy-5- (4-oxo-3- (2-pyrazol-1-yl-ethoxy) pyrido [1,2-a] pyrimidin7-yl) pyridin- 3-yl) benzenesulfonamide

a) 7-Bromo-3- (2-bromoethoxy) pyrido [1,2-a] pyrimidin-4-one.

7-Bromo-3-hydroxypyrido [1,2-a] pyrimidin-4-one (600.00 mg, 2.49 mmol) and 1,2-dibromoethane (1.40 g, 7.47 mmol) were dissolved in ΏΜΕ (10 ml) and potassium carbonate was added (1.03 g, 7.47 mmol). The mixture was stirred to start the reaction at 100 ° C for 1.5 h. TBS showed that the reaction was completed, and then the reaction solution was cooled to room temperature. The resulting solution was purified by silica gel column chromatography to obtain the title compound (550.00 mg, 63.5%) as a brown solid.

¹ H NMR (400 MHz, COC1 ₃ ) ppm 9.10 (δ, 1 H), 8.20 (δ, 1H), 7.61 (άά, 1 = 9.54, 1.71 Hz, 1H), 7.49 (ά, 1 = 9.54 Hz, 1H ), 4.49 (ΐ, 1 = 6.36 Hz, 2Н), 3.66 (ΐ, 1 = 6.36 Hz, 2Н).

b) L- (5- (3- (2-Bromoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4 difluorobenzenesulfonamide.

7-Bromo-3- (2-bromoethoxy) pyrido [1,2-a] pyrimidin-4-one (550.00 mg, 1.58 mmol) was dissolved in wild

34,032,642 sane (15 ml) and water (2 ml), and then 2,4-difluoro-No (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2) was added -yl) pyridin-3-yl) benzenesulfonamide (673.67 mg, 1.58 mmol), potassium carbonate (436.74 mg, 3.16 mmol) and 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (117.20 mg, 158.00 mmol) in a protective atmosphere nitrogen. The mixture was stirred to start the reaction at 90 ° C for 1.5 hours. Liquid chromatography-mass spectrometry showed that the reaction was completed. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the title compound (250.00 mg, 27.89%) as a pale yellow solid.

¹ H NMR (400 MHz, COC1 ₃ ) ppm 9.03 (8, 1 H), 8.24 (8, 1 H), 8.12 (ά, 1 = 2.20 Hz, 1H), 7.89-7.98 (t, 2H), 7.68- 7.76 (t, 2H), 7.32 (L8, 1H), 6.99-7.06 (t, 1H), 6.90-6.98 (t, 1H), 4.52 (ΐ, 1 = 6.24 Hz, 2 H), 3.98 ( δ, 3 N), 3.69 (ΐ, 1 = 6.36 Hz, 2 N).

c) 2,4-Difluoro-No. (2-methoxy-5- (4-oxo-3- (2-pyrazol-1-yl-ethoxy) pyrido [1,2-a] pyrimidin-7-yl) pyridin- 3-yl) benzenesulfonamide.

No. (5- (3- (2-Bromoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2-methoxypyridin-3-yl) -2,4 difluorobenzenesulfonamide (50.00 mg, 88.13 μmol) and 1H-pyrazole (9.00 mg, 132.20 μmol) were dissolved in acetonitrile (0.5 ml) and then cesium carbonate (57.43 mg, 176.26 μmol) was added. The mixture was stirred to start the reaction at 70 ° C for 2 hours. Liquid chromatography-mass spectrometry showed that the reaction was completed. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified using preparative high performance liquid chromatography to give the title compound (15.00 mg, 30.69%) as a yellow solid.

¹ H NMR (400 MHz, COC1 ₃ ) ppm 9.00 (ά, 1 = 0.98 Hz, 1H), 8.11 (ά, 1 = 2.20 Hz, 1H), 7.87-7.99 (t, 3H), 7.61-7.73 (t, 3H), 7.49-7.57 (t, 1H), 7.34 (L8, 1H), 6.98-7.06 (t, 1H), 6.90-6.98 (t, 1H), 6.26 (ΐ, 1 = 1.96 Hz, 1H), 4.57 (άά, 1 = 10.88, 4.28 Hz, 4 N), 3.97 (8, 3 N).

The following 3 compounds were also synthesized in accordance with the method for producing compound 37.

Compound Structure M8 (E8) [M + H] ⁺ 38 .ABOUT. ⁰ 0 = 3 = 0 E 569 39 X> ° 0 = 3 = 0 ’-Ψ“ E 623 40 ABOUT O = 8 = O £ Ν == / at E 569

Reaction conditions: a) methanesulfonyl chloride, triethylamine, dichloromethane, from 0 ° C to

- 35 032642 room temperature; B) potassium carbonate; ΌΜΡ heating; c) Borate (boric acid), 1,1'bis (diphenylphosphino) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating; b) hydrochloric acid - ethyl acetate, ethyl acetate, room temperature.

Example 41. 2,4-Difluoro - ^ (2-methoxy-5- (4-oxo-3- (piperidin-4-yloxy) -4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin- 3-yl) benzenesulfonamide

ΝΗ

a) tert-Butyl 4 - ((methylsulfonyl) oxy) piperidine-1-carboxylate.

Tert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) and triethylamine (1 g, 9.95 mmol) were dissolved in dichloromethane (4 ml), and then methanesulfonyl chloride (1 g, 8.72 mmol) was added dropwise at 0 ° WITH. After completion of the dropwise addition, the reaction solution was warmed to room temperature and stirred to start the reaction for 2 hours. The reaction solution was poured into ice water to stop the reaction, and the resulting mixture was extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain the title compound (1.6 g, crude product) as a red solid.

b) tert-Butyl 4 - ((7-bromo-4-oxo-4H-pyrido [1,2-a] pyrimidin-3-yl) oxy) piperidine-1-carboxylate.

tert-Butyl 4 - ((methylsulfonyl) oxy) piperidine-1-carboxylate (200 mg, 0.72 mmol), 7-bromo-3-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one (115 mg, 0.48 mmol) and potassium carbonate (198 mg, 1.43 mmol) were dissolved in Ν, Ν-dimethylformamide (2 ml). The mixture was stirred to start the reaction at 120 ° C. for 2 hours under a protective nitrogen atmosphere. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to give the title compound (170 mg, 84%) as a red solid.

¹ H NMR (400 MHz, SOSI) ppm 9.14-9.10 (t, 1 H), 8.17 (8, 1 H), 7.65-7.59 (t, 1 H), 7.53-7.47 (t, 1 H), 4.90- 4.88 (t, 1H), 3.85 (t, 2H), 3.71-3.70 (t, 2H), 1.95 (8, 3H), 1.47 (8, 9H).

c) tert-Butyl 4 - ((7- (5- (2,4-difluorobenzenesulfonamido) -6-methoxypyridin-3-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-3-yl ) hydroxy) piperidine-1-carboxylate.

tert-Butyl 4 - ((7-bromo-4-oxo-4H-pyrido [1,2-a] pyrimidin-3-yl) oxy) piperidine-1-carboxylate (130 mg, 0.3 mmol), 2,4- difluoro ^ - (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3yl) benzenesulfonamide (130 mg, 0.3 mmol), potassium carbonate (85 mg, 0.61 μmol) and 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (22 mg, 0.03 mmol) were dissolved in dioxane (2 ml) and water (0.4 ml). The reaction solution was stirred at 100 ° C for 2 h in a protective atmosphere of nitrogen and under microwave conditions. The crude product was purified by silica gel column chromatography to give the title compound (80 mg, 30%) as a red oil.

b) 2,4-Difluoro - ^ (2-methoxy-5- (4-oxo-3- (piperidin-4-yloxy) -4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3 -yl) benzenesulfonamide hydrochloride tert-Butyl 4 - ((7- (5- (2,4-difluorobenzenesulfonamido) -6-methoxypyridin-3-yl) -4-oxo-4H-pyrido [1,2-a] pyrimidine- 3-yl) oxy) piperidine-1-carboxylate (28 mg, 0.043 mmol) was dissolved in ethyl acetate (2 ml) and hydrochloric acid / ethyl acetate (15 ml) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered, and the solid was evaporated to dryness on a rotary evaporator to give the title product (7.4 mg, 29%) as a brown solid. 1Н NMR (400 MHz, SB ₃ СУ) ррт 9.24 (8, 1Н), 8.47-8.46 (t, 2Н), 8.37 (8, 1Н), 8.13 (8, 1Н), 7.97-7.86 (t, 2 Н) , 7.26-7.21 (t, 1H), 7.12-7.08 (t, 1H), 4.85-4.84 (t, 1H), 3.86 (8, 1H), 3.553.50 (t, 2 H), 3.31-3.25 (t , 2 N), 2.19 (8, 4 N).

The following 3 compounds were also synthesized in accordance with the method for producing compound 41:

- 36,032,642

Reaction conditions: a) 5-bromo-2-chloro-3-nitropyridine, K alcohol, potassium hydroxide, potassium carbonate, 2- (2-methoxyethoxy) -M, N-di [2- (2-methoxyethoxy) ethyl] ethanamine, toluene; B) 4,4,5,5-tetramethyl2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolan, 1,1 'bis (diphenylphosphino) ferrocene palladium chloride, potassium acetate, dioxane, heating; c) Rb / C, methanol; b) 7-bromo-3-chloro-pyrido [1,2a] pyrimidin-4-one, 1,1'-bis (diphenylphosphino) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating; e) 2,4-difluorobenzenesulfonyl chloride, pyridine; ί) hydrochloric acid / dioxane, dioxane.

Example 45. N- [5- (3-chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2- (3- (methylamino) propoxy) pyridin-3-yl] -2,4-difluoro-benzenesulfonamide

a) tert-Butyl (3 - ((5-bromo-3-nitropyridin-2-yl) oxy) propyl) (methyl) carbamate.

To a mixture of a solution of potassium hydroxide (723 mg, 12.89 mmol) and potassium carbonate (1.78 g, 12.89 mmol) in toluene (30 ml) was added 5-bromo-2-chloro-3-nitropyridine (1.8 g, 7.58 mmol), tert- butyl (3-hydroxypropyl) (methyl) carbamate (1.72 g, 9.1 mmol) and 2- (2-methoxyethoxy) -M, N-di [2- (2-methoxyethoxy) ethyl] ethanamine (245 mg, 0.758 mmol). The mixture was stirred at 15 ° C for 18 hours under a protective atmosphere of nitrogen. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated and then purified by silica gel column chromatography (PE: EA = 20: 1-4: 1) to obtain the title compound (1.5 g, 50%) as a yellow oil.

¹ H NMR (400 MHz, SES13) ppm δ 8.40 (b, .12.0 Hz, 1H), 8.36 (b, .12.2 Hz, 1H), 4.47 (I, .1 6.1 Hz, 2H), 3.40 (ί, 1 = 6.8 Hz, 2H), 2.87 (8, 3H), 2.03 (8.2H), 1.41 (5, 9H).

b) tert-Butyl methyl (3 - ((3-nitro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) oxy) propyl) carbamate.

In a protective atmosphere of nitrogen to a mixture of a solution of tert-butyl (3 - ((5-bromo-3-nitropyridin-2-yl) oxy)

- 37 032642 propyl) (methyl) carbamate (1.5 g, 3.84 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- il) -1,3,2-dioxaborolan (1.17 g, 4.61 mmol) and potassium acetate (1.13 g, 11.53 mmol) in dioxane (30 ml) 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (97 mg, 0.11 mmol). The mixture was stirred at 80 ° C. for 18 hours under a nitrogen blanket. After determining the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated and then purified by silica gel chromatography to give a crude product (0.9 g, 53%) as a yellow oil.

Ίί NMR (400 MHz, СОС13) ppm 8.65 (ά, 1 = 1.5 Hz, 1Н), 8.55 (ά, 1 = 1.5 Hz, 1Н), 4.52 (ΐ, 1 = 5.7 Hz, 2Н), 3.41 (ΐ, 1 = 6.8 Hz, 2H), 2.87 (5, 3H), 2.04 (L5, 2H), 1.41 (5, 9H), 1.33 (5, 12H).

c) tert-Butyl (3 - ((3-amino-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) oxy) propyl) ( methyl) carbamate.

Ρά / C (90.00 mg) was added to a solution of tert-butyl methyl (3 - ((3-nitro-5 - (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) pyridin-2- il) oxy) propyl) carbamate (900 mg, 2.06 mmol) in methanol (10 ml). The mixture was stirred at 15 ° C. for 4 hours under a hydrogen atmosphere. After determining the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated to obtain a crude product (870 mg, 95%) as a yellow oil.

1 H NMR (400 MHz, COC13) ppm δ 7.93 (5, 1H), 7.21 (5, 1H), 4.41 (ΐ, 1 = 6.0 Hz, 2H), 3.39 (bg. 5., 2H), 2.85 (bg. 5., 3H), 2.00 (bg. 5., 2H), 1.41 (bg. 5., 9H), 1.31 (5, 12H).

ά) tert-Butyl (3 - ((3-amino-5- (3-chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-2-yl) oxy) propyl ) (methyl) carbamate.

In a protective atmosphere of nitrogen to a mixture of a solution of 7-bromo-3-chloro-pyrido [1,2-a] pyrimidin-4-one (503 mg, 1.94 mmol), tert-butyl (3 - ((3-amino-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-yl) oxy) propyl) (methyl) carbamate (790 mg, 1.94 mmol) and sodium carbonate (1 M , 4.85 ml, 4.85 mmol) in dioxane (10 ml) was added 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (17 mg, 0.019 mmol) at room temperature. The mixture was stirred at 80 ° C. for 18 hours under a nitrogen blanket. After determining the completion of the reaction, the reaction solution was filtered, and the filtrate was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (600 mg, 67%) as a yellow solid.

'II NMR (400 MHz, СОС13) δ 9.18 (ά, 1 = 1.7 Hz, 1Н), 8.48 (5, 1Н), 7.97 (άά, 1 = 2.1, 9.2 Hz, 1Н), 7.84-7.66 (t, 2Н ), 7.13 (ά, 1 = 1.7 Hz, 1H), 4.45 (bg. 5., 2H), 3.43 (bg. 5., 2H), 2.88 (bg. 5., 3H), 2.05 (ΐ, 1 = 6.5 Hz, 2H), 1.43 (5, 9H).

f) tert-Butyl (3 - ((5- (3-chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -3- (2,4-difluorobenzenesulfonamido) pyridin-2 -yl) hydroxy) propyl) (methyl) carbamate.

2,4-Difluorobenzenesulfonyl chloride (333 mg, 1.57 mmol) was added to the mixture of a solution of tert-butyl (3 ((3-amino-5- (3-chloro-4-oxo-4H-pyrido [1,2-a] pyrimidine- 7-yl) pyridin-2-yl) oxy) propyl) (methyl) carbamate (600 mg, 1.3 mmol) in pyridine (5 ml). The mixture was allowed to react at 15 ° C for 18 hours. After completion of the reaction, the reaction solution was concentrated. The residue was dissolved in dichloromethane and washed with water and brine. The organic phase was dried over anhydrous sodium sulfate and then concentrated. The resulting product was purified by silica gel chromatography to give the title compound (404 mg, 48%) as a yellow solid.

ί) Ν- [5- (3-Chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -2- (3- (methylamino) propoxy) pyridin-3yl] -2, 4-difluorobenzenesulfonamide.

To a solution of tert-butyl (3 - ((5- (3-chloro-4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) -3- (2,4-difluorobenzenesulfonamido) pyridin-2 -yl) hydroxy) propyl) (methyl) carbamate (450 mg, 0.43 mmol) in dioxane (30 ml) was added a solution of hydrochloric acid / dioxane (4 ml). The mixture was stirred at 15 ° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated. An aqueous sodium bicarbonate solution was added to the concentrated residue. The precipitate was filtered off and pumped to dryness, and washed with dichloromethane to give the title compound as a pale yellow solid (175.56 mg, 75.9%).

Ίί NMR (400 MHz, ΌΜ8Ο-ά ₆ ) δ 8.81 (ά, 1 = 1.5 Hz, 1Н), 8.56 (5, 1Н), 8.13 (άά, 1 = 2.0, 9.3 Hz, 1Н), 8.027.89 (t , 1H), 7.85-7.73 (t, 2H), 7.47 (ά, 1 = 2.2 Hz, 1H), 7.33-7.21 (t, 1H), 7.19-7.09 (t, 1H), 4.29 (ΐ, 1 = 5.4 Hz, 2H), 3.20-3.08 (t, 2H), 2.72 (5, 3H), 2.08 (t, 2H).

The following 5 compounds were also synthesized in accordance with the method for producing compound 45:

- 38 032642

Reaction conditions:

a) diethylethoxymethylene malonate, ethanol, heating; B) phosphorus oxybromide, heating; c) ΌΙΒΆΕH, tetrahydrofuran, -5 ° C-0 ° C; ά) manganese dioxide, dioxane, heating; (e) morpholine, sodium triacetoborohydride, acetic acid, methanol, heating; ί) No. [2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) pyridin-3-yl] -2,4-dimethyl-5-sulfonamide, 1, 1 'bis (diphenylphosphino) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating.

Example 51. No. (2-Methoxy-5- (3- (morpholinomethyl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) -2,4-dimethylthiazole -5-sulfonamide

- 39 032642

a) Diethyl 2 - (((5-bromopyridin-2-yl) amino) methylene) malonate.

2-amino-5-bromopyridine (1.72 g, 9.94 mmol) and diethylethoxymethylene malonate (4.51 g, 20.87 mmol) were placed in a round bottom flask, and the mixture was stirred to start the reaction at 130 ° C for 2 h. TBS showed that the reaction was complete, and then the mixture was cooled to 25 ° C and filtered. The filter cake was washed with petroleum ether (20 ml x 3) to give the title compound (3.14 g, 92%) as a white solid.

¹ NMR (400 MHz, ATP1 ₃ ) ppm 11.10 (b, 6 = 12.47 Hz, 1H), 9.06 (b, 1 = 12.72 Hz, 1H), 8.38 (b, 1 = 2.20 Hz, 1H), 7.74 (bb, 1 = 8.56, 2.45 Hz, 1H), 6.76 (b, 1 = 8.56 Hz, 1H), 4.21-4.34 (t, 4H), 1.35 (b1, 1 = 16.02, 7.15 Hz, 6 N).

b) Ethyl 7-bromo-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carboxylate.

Diethyl 2 - (((5-bromopyridin-2-yl) amino) methylene) malonate (21.76 g, 63.41 mmol) and phosphorus oxybromide (54.54 g, 190.23 mmol) were placed in a round bottom flask, and the mixture was stirred to start the reaction at 80 ° C for 4 hours. TBS showed that the reaction was completed. The mixture was cooled to 25 ° C. and then slowly added to ice water. An aqueous solution of sodium carbonate was added to the mixture, and the pH was adjusted to about 8. The resulting mixture was extracted with dichloromethane (300 ml x 3), and the organic phase was washed with saturated brine (200 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (18.8 g, 99.8%) as a white solid.

¹ H NMR (400 MHz, SPS1 ₃ ) ppm 9.36 (b, 1 = 1.98 Hz, 1H), 9.03 (8, 1 H), 7.97 (bb, 1 = 9.26, 1.98 Hz, 1H), 7.67 (b, 1 = 9.26 Hz, 1H), 4.42 (ς, 1 = 7.06 Hz, 2 N), 1.41 (ΐ, 1 = 7.06 Hz, 3 N).

c) 7-Bromo-3- (hydroxymethyl) -4H-pyrido [1,2-a] pyrimidin-4-one.

Ethyl 7-bromo-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carboxylate (5.00 g, 16.83 mmol) was dissolved in tetrahydrofuran (150 ml) and placed in a three-necked round-bottom flask. A solution of ΏΙΒΑΕ-Η (50.49 mmol) in toluene (50 ml) was added dropwise to the above mixture at -5 ° C. The reaction solution was stirred at 0 ° C for 2 hours. TEC showed that the reaction was complete. A saturated aqueous solution of ammonium chloride was slowly added to the reaction solution, and the resulting mixture was extracted with ethyl acetate (200 ml x 3), washed with saturated brine (200 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the title compound (1.1 g, 25.6%) as a brick red solid.

¹ H NMR (400 MHz, ATP1 ₃ ) ppm 9.15 (b, 1 = 1.96 Hz, 1H), 8.39 (8, 1 H), 7.98 (bb, 1 = 9.54, 2.20 Hz, 1H), 7.59 (b, 1 = 9.29 Hz, 1H), 4.64 (δ, 2H).

b) 7-Bromo-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carbaldehyde.

7-Bromo-3- (hydroxymethyl) -4H-pyrido [1,2-a] pyrimidin-4-one (0.7 g, 2.74 mmol) dissolved in dioxane (15 ml) was placed in a 50 ml round bottom flask, and manganese dioxide (2.39 g, 27.44 mmol) was added to it. The mixture was stirred to start the reaction at 80 ° C. for 3 hours. TBS showed that the reaction was complete and the reaction solution was cooled to room temperature. The reaction solution was diluted with dichloromethane (50 ml) and filtered. The filtrate was concentrated to obtain the title compound (0.6 g, 86.5%) as a yellow solid.

¹ H NMR (400 MHz, ATP1 ₃ ) ppm 10.38 (8, 1 H), 9.39 (b, 1 = 2.21 Hz, 1H), 8.90 (8, 1 H), 8.06 (bb, 1 = 9.26, 2.21 Hz, 1H), 7.73 (b, 1 = 9.26 Hz, 1H).

e) 7-Bromo-3- (morpholinomethyl) -4H-pyrido [1,2-a] pyrimidin-4-one.

7-Bromo-4-oxo-4H-pyrido [1,2-a] pyrimidine-3-carbaldehyde (88.00 mg, 347.75 μmol) dissolved in methanol (4 ml) was placed in a 10 ml vial with a lid, and to it Morpholine (45.44 mg, 521.63 μmol) and AcOH (41.77 mg, 695.51 μmol) were added. The mixture was stirred at 50 ° C. for 2 hours. Sodium triacetoborohydride (294.81 mg, 1.39 mmol) was added to the above reaction solution, and stirring was continued at 50 ° C. for 12 hours. TBS indicated that the reaction was complete, and then the reaction solution was cooled to room temperature, and purified by silica gel column chromatography to give the title compound (45 mg, 40%) as a yellow solid.

¹ H NMR (400 MHz, ATP1 ₃ ) ppm 9.13 (b, 1 = 1.71 Hz, 1H), 8.38 (δ, 1H), 7.70 (bb, 1 = 9.41, 2.08 Hz, 1H), 7.49 (b, 1 = 9.29 Hz, 1H), 3.68-3.73 (t, 4H), 3.62 (δ, 2H), 2.57 (L8, 4H).

1) K- (2-Methoxy-5- (3- (morpholinomethyl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) -

2,4-dimethylthiazole-5-sulfonamide.

7-Bromo-3- (morpholinomethyl) -4H-pyrido [1,2-a] pyrimidin-4-one (60.00 mg, 185.09 mmol) dissolving

40,032,642 whether in dioxane (3 ml) and water (0.5 ml) and No. [2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine was added -3-yl] -2,4-dimethylthiazole-5-sulfonamide (86.60 mg, 203.60 μmol), potassium carbonate (51.16 mg, 370.18 μmol) and 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (13.54 mg, 18.51 μmol) in a protective atmosphere of nitrogen. The mixture was stirred to start the reaction at 80 ° C for 2 hours. Liquid chromatography-mass spectrometry showed that the reaction was completed. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified using preparative high performance liquid chromatography to give the title compound (50.00 mg, 50%) as a yellow solid.

¹ Η NMR (400 MHz, SESR rt 9.23 (8, 1 Η), 8.42 (8, 1 Η), 8.20 (ά, 1 = 1.76 Hz, 1Η), 8.06 (8, 1 Η), 7.90 (άά, 1 = 9.04, 1.76 Hz, 1Η), 7.77 (ά, 1 = 9.04 Hz, 1Η), 4.00 (8, 3Η), 3.76 (ΐ, 1 = 4.41 Hz, 4 Η), 3.65 (8, 2Η), 2.66 ( 8, 3Η), 2.59 (8, 7 Η).

The following 1 compound was also synthesized in accordance with the method of obtaining compound 51.

Reaction conditions: a) malonyl chloride, dichloromethane, room temperature; B) phosphorus oxychloride, reflux; c) No. (2-hydroxypropyl) morpholine, sodium hydride, tetrahydrofuran, from 0 ° C to room temperature; ά) K borate (boric acid), 1,1'-bis (diphenylphosphino) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating.

Example 53. 2-Chloro-4-fluoro ^ - (2-methoxy-5- (2- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrido

a) 7-Bromo-2-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one.

2-amino-5-bromopyridine (1.0 g, 5.7 mmol) dissolved in dichloromethane (10 ml) was placed in a 50 ml round bottom flask. Malonyl chloride (977 mg, 6.9 mmol) was added dropwise at 0 ° C. After completion of the dropwise addition, the reaction solution was heated to 15 ° C and stirred to start the reaction at 15 ° C for 48 hours. LC / MS showed that the reaction was completed. The reaction solution was filtered, and the filter cake was washed with dichloromethane (20 ml) to obtain the title compound (1.4 g, 100%) as a yellow solid.

b) 7-Bromo-2-chloro-4H-pyrido [1,2-a] pyrimidin-4-one.

7-Bromo-2-hydroxy-4H-pyrido [1,2-a] pyrimidin-4-one (900 mg, 3.73 mmol) dissolved in phosphorus oxychloride (8 ml) was placed in a 50 ml round bottom flask, and the mixture was stirred to start the reaction at 110 ° C for 18 hours. LC / MS showed that the reaction was completed. The reaction solution was cooled to room temperature, and slowly poured into water at ordinary temperature (50 ml) to stop the reaction, and the resulting mixture was extracted with ethyl acetate (20 ml x 3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified using column chromatography

41,032,642 on silica gel to give the title compound (300 mg, 31%) as a yellow solid.

¹ H NMR (400 MHz, BM8O-66) rph 8.99 (b, 1 H), 8.21 (bb, 1 H), 7.65 (b, 1 H), 6.56 (5, 1 N).

c) 7-Bromo-2- (2-morpholinoethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one.

No. (2-Hydroxypropyl) morpholine (404 mg, 3.08 mmol) dissolved in tetrahydrofuran (5 ml) was placed in a 50 ml round bottom flask, sodium hydride (308 mg, 7.71 mmol, 60% purity) was added at 0 ° C, and the reaction mixture was stirred at 0 ° C for 30 minutes. Then 7-bromo-2- (2-morpholinoethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one (200 mg, 770 μmol) was added dropwise. The reaction solution was heated to 15 ° C, and the mixture was stirred to start the reaction for 3 hours. TJ showed that the reaction is complete. The reaction solution was slowly poured into ice water (50 ml) to stop the reaction, and the resulting mixture was extracted with ethyl acetate (20 ml x 3). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified using preparative thin layer chromatography to give the title compound (40 mg, 14%).

b) 2-Chloro-4-fluoro-X- (2-methoxy-5- (2- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7yl) pyridin-3- il) benzenesulfonamide.

7-Bromo-2- (2-morpholinoethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one (70 mg, 197 μmol) was dissolved in dioxane (5 ml) and water (1 ml) and 2 -chloro-4-fluoro-X- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (87 mg, 197 μmol ), potassium carbonate (54 mg, 395 μmol) and 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (7 mg). The reaction solution was stirred at 100 ° C. for 3 hours under a protective nitrogen atmosphere. LC / MS showed that the reaction is complete. The reaction solution was concentrated to obtain a crude product. The crude product was purified using preparative high performance liquid chromatography to give the title compound (50 mg, 42%) as a white solid.

¹ H NMR (400 MHz, SESU rrsh 9.08 (b, 1 H), 8.14 (bb, 1 H), 8.09 (b, 1 H), 7.90 (b, 1 H), 7.87 (bb, 1 H), 7.58 (b , 2H), 7.28 (b, 1H), 7.19-7.12 (w, 1H), 5.86 (5, 1H), 4.58-4.48 (w, 2H), 3.99 (5, 3H), 3.76 (Lg. 5. , 4 H), 2.85 (Lt. 5, 2 H), 2.62 (Lt. 5, 3H).

Reaction conditions: a) triphosgene, triethylamine, 2,4-dimethyl-5-aminothiazole, 0 ° C; anhydrous dichloromethane, room temperature; B) 1,1'-bis (diphenylphosphino) ferrocene palladium chloride, potassium acetate, bis (pinacolato) diborone, anhydrous dioxane, heating; c) 1- (2-methoxy-5-bromopyridin-3yl) -3- (2,4-dimethylthiazol-5-yl) urea, 1,1'-bis (di-tert-butylphosphino) ferrocene palladium dichloride, potassium phosphate trihydrate, tetrahydrofuran, water and heating.

Example 54. 1 - (2,4-Dimethylthiazol-5-yl) -3- (2-methoxy-5- (3- (2-morpholinoethyl) -4-oxo-4H-pyrido [1,2-a] pyrimidine -7-yl) pyridin-3-yl) urea

a) 1- (2-Methoxy-5-bromopyridin-3-yl) -3- (2,4-dimethylthiazol-5-yl) urea.

2-Methoxy-3-amino-5-bromopyridine (100.00 mg, 492.52 μmol), triethylamine (498.38 mg, 4.93 mmol) and anhydrous dichloromethane (5 ml) were placed in a 10 ml three-necked round-bottom flask, a solution of triphosgene (438.47 was slowly added dropwise. mg, 1.48 mmol) in dichloromethane (1 ml) at 0 ° C in a protective atmosphere of nitrogen, and the mixture was stirred to start the reaction at room temperature for 2 hours. 2,4-Dimethyl-5-aminothiazole (162.20 mg, 985.04 mmol) was added at 0 ° C in a protective atmosphere of nitrogen, and the reaction mixture was stirred at room temperature overnight. Liquid chromatography-mass spectrometry showed that the reaction was complete, then water (50 ml) was added to the mixture, and the resulting mixture was extracted with dichloromethane (50 ml x 3). The organic phases were combined, washed with saturated brine (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the title compound (85.00 mg, 48%) was obtained with

- 42 032642 general chromatography on silica gel.

¹ H NMR (400 MHz, SEZOE) ppm δ 8.57 (ά, 1H), 7.82 (ά, 1H), 4.02 (s, 3H), 2.56 (δ, 3H), 2.26 (δ, 3H).

b) (3- (2-Morpholinoethyl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) boronic acid.

7-Bromo-3- (2-morpholinoethyl) -4H-pyrido [1,2-a] pyrimidin-4-one (200.00 mg, 564.65 μmol) was placed in a 10 ml long-necked round-bottom flask and dissolved in dioxane (3 ml) at room temperature. Then, bis (pinacolato) diboron (430.16 mg, 1.69 mmol), potassium acetate (221.57 mg, 2.26 mmol) and 1,1'-bis (diphenylphosphino) ferrocene palladium dichloride (41.32 mg, 56.47 μmol) were added in a protective nitrogen atmosphere. The mixture was allowed to react at 100 ° C for 2 hours. Liquid chromatography-mass spectrometry showed that the reaction was completed. The reaction solution was diluted with ethyl acetate (20 ml) and extracted with water (20 ml x 3). The aqueous phases were combined and concentrated to give the title compound (120.00 mg, crude product). The crude product was used directly in the next reaction without further purification. B) 1- (2,4-Dimethylthiazol-5-yl) -3- (2-methoxy-5 (3- (2-morpholinoethyl) -4-oxo-4H-pyrido.

c) [1,2-a] Pyrimidin-7-yl) pyridin-3-yl) urea.

To a solution of (3- (2-morpholinoethyl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) boronic acid (120.00 mg, crude product) in tetrahydrofuran (4 ml) and water (1 ml) was added 1 - (2-methoxy-5bromopyridin-3-yl) -3- (2,4-dimethylthiazol-5-yl) urea (30.00 mg, 83.98 μmol), potassium phosphate trihydrate (38.68 mg, 167.96 μmol) and 1,1'-bis (di-tert-butylphosphino) ferrocene palladium dichloride (5.47 mg, 8.40 μmol). The mixture was allowed to react at 80 ° C for 5 hours. Liquid chromatography-mass spectrometry showed that the reaction was completed. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified using preparative high performance liquid chromatography to give the title compound (24.00 mg, 52%).

¹ H NMR (400 MHz, ΠΜ8Θ-ά ₆ ) ppm δ 8.92 (ά, 1H), 8.73 (ά, 1H), 8.18 (δ, 1H), 8.13 (ά, 1H), 8.01-8.03 (t, 1H) , 7.66 (ά, 1H), 4.19-4.22 (t, 2H), 4.01 (δ, 3H), 3.54-3.56 (t, 4H), 2.67-2.70 (t, 2H), 2.45-2.49 (t, 7H) 2.23 (δ, 3H).

The following 1 compound was also synthesized in accordance with the method of obtaining compound 54.

Pattern 10

Reaction conditions:

a) sulfoxide chloride, dichloromethane, room temperature; B) 7- (5-amino-6-methoxypyridin-3yl) -3- (2-morpholinoethoxy) -4H-pyrido [1,2-a] pyrimidin-4-one, ΏΜΡ, heating.

Example 56. ^ D-MethoxyA-O-D-morpholinoethoxyN-oxoL! 1-11irido | 1,2-a | 11irimidin-7-yl) pyridin-3-yl) -2,4-dimethylthiazole-5-carboxamide

N \ S neg. Oipb 5 6

a) 2,4-Dimethylthiazole-5-carbonyl chloride.

2,4-Dimethylthiazole-5-carboxylic acid (50.0 mg, 0.318 mmol) and dichloromethane (2 ml) were placed in a 10 ml round bottom flask, sulfoxide chloride (378.43 mg, 3.18 mmol) was added at 0 ° C, and the mixture was stirred to start reaction at room temperature for 1 h. TBS showed that the reaction is complete. The mixture was concentrated to obtain the title compound as a black solid, which was directly used in the next reaction without further purification.

b) N- (2-Methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3yl) -2,4-dimethylthiazole -5-carboxamide.

- 43,032,642

2,4-Dimethylthiazole-5-carbonyl chloride (50.0 mg, 0.284 mmol), 7- (5-amino-6-methoxypyridin-3-yl) 3- (2-morpholinoethoxy) -4H-pyrido [1,2-a ] pyrimidin-4-one (113.1 mg, 0.284 mmol) and ΌΜΡ (0.5 ml) were placed in a 10 ml round bottom flask, and the reaction mixture was stirred at 60 ° C for 0.5 h. TLC showed that the reaction was completed, and then the reaction solution cooled to room temperature and purified using preparative thin layer chromatography plate to give the title compound (10 g, 80%).

'H NMR (400 MHz, SOeOO) ppm δ 9.19 (8, 1H), 8.82 (ά, 1H), 8.35-8.37 (t, 1H), 8.16-8.19 (t, 1H), 7.81 (ά, 1H), 4.50-4.52 (t, 2Н), 4.13 (8, 3Н), 3.97 (8, 4Н), 3.59 (8, 1 Н), 3.49 (8, 1 Н), 2.73 (ά, 1 Н).

The following 1 compound was also synthesized in accordance with the method of obtaining compound 56.

Compound Structure M8 (E8) [M + H] ⁺ 57 XX A1 ⁰ Η N ν RAL _C1 554

Reaction conditions: a) triethylamine, diphenylphosphoryl azide, tert-butanol, heating; B) hydrochloric acid-ethyl acetate, room temperature; c) chlorosulfonic acid, heating; ά) pyridine, 2,4-dimethyl-5-aminothiazole, dioxane, heating; e) sodium nitrite, concentrated hydrochloric acid, ice bath; ί) sodium methoxide, methanol, heating; e) bis (pinacolato) diboron, 1,1'bis (diphenylphosphino) ferrocene palladium chloride, potassium acetate, dioxane, heating; B) (3- (2morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) boronic acid, 1,1'-bis (diphenylphosphino) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating.

Example 58. No. (2,4-Dimethylthiazol-5-yl) -2-methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-4H-pyrido [1, 2-a] pyrimidin-7 -yl) pyridin-3-sulfonamide

a) tert-Butyl (2,4-dimethylthiazol-5-yl) carbamate.

2,4-Dimethylthiazole-5-carboxylic acid (700.00 mg, 4.45 mmol), diphenylphosphoryl azide (1.65 g, 6.00 mmol), triethylamine (1.13 g, 11.13 mmol) and tert-butanol (35 ml) were placed in a 100 ml round-bottomed one-necked flask and the mixture was stirred to start the reaction at 85 ° C for 4 hours. TBS showed that the reaction was complete. The reaction solution was cooled to room temperature, H2O (20 ml) was added thereto, and the resulting mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to dryness on a rotary evaporator. The resulting crude product was purified by silica gel column chromatography to give the title compound (900.00 mg, 88.54%).

¹ H NMR (400 MHz, [) M8 O-s1 ₍₁ ) δ 9.46 (L8, 1H), 2.46 (8, 3H), 2.14 (8, 3H), 1.43 (8, 9H).

- 44 032642

b) 2,4-Dimethyl-5-aminothiazole hydrochloride.

tert-Butyl (2,4-dimethylthiazol-5-yl) carbamate was dissolved in hydrochloric acid-ethyl acetate (10 ml). The solution was stirred at room temperature for 1 h and then evaporated to dryness on a rotary evaporator. The resulting crude product was suspended with ethyl acetate to give the title compound (700 mg). ¹ H NMR (400 MHz, ΌΜ80-ά ₆ ) δ 2.66 (§, 3H), 2.19 (δ, 3H).

c) 2-amino-5-bromopyridin-3-sulfonyl chloride.

Chlorosulfonic acid (136.18 g, 57.80 mmol) was placed in a 250 ml round bottom three-necked flask and cooled to -15 ° C, and then 2-amino-5-bromopyridine (10.00 g, 57.80 mmol) was added dropwise in a protective atmosphere of nitrogen. After completion of the dropwise addition, the resulting mixture was gradually heated to 160 ° C. in an oil bath and stirred for 5 hours while heating. After completion of the reaction, the reaction mixture was cooled to room temperature and slowly poured onto ice. After the ice melted, the precipitated solid was filtered and washed with ice water to obtain the title compound (10.00 g, 63.72%). 'H NMR (400 MHz, ΌΜ80-ά ₆ ) δ 8.27 (ά, 1 = 2.3 Hz, 1Н), 8.08 (ά, 1 = 2.0 Hz, 1Н).

ά) 2-amino-5-bromo-no. (2,4-dimethylthiazol-5-yl) pyridin-3-sulfonamide.

A solution of 2-amino-5-bromopyridin-3-sulfonyl chloride (164.90 mg, 607.33 mmol) in dioxane (3 ml) was placed in a 50 ml round-bottomed three-necked flask and cooled to 0 ° C, and pyridine (196.00 mg, 2.48 mmol) was added to it. ) and 2,4-dimethyl-5-aminothiazole hydrochloride (100.00 mg, 607.33 mmol). The reaction solution was gradually warmed to room temperature and stirred for 2 hours, and then heated to 50 ° C and allowed to react for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and dissolved in a mixture of dichloromethane and methanol (dichloromethane: methanol = 20: 1). After stirring for 30 minutes, the mixture was filtered, the resulting filtrate was evaporated to dryness on a rotary evaporator, and the resulting crude product was purified by silica gel column chromatography to obtain the title compound (60.00 mg, 27.20%).

^! H NMR (400 MHz, (Ί®01)) δ 8.27 (ά, 1 = 2.5 Hz, 1H), 7.81 (ά, 1 = 2.5 Hz, 1H), 2.56 (δ, 3H), 2.06 (δ, 3H) .

e) 2-Chloro-5-bromo-No (2,4-dimethylthiazol-5-yl) pyridin-3-sulfonamide.

2-amino-5-bromo-no. (2,4-dimethylthiazol-5-yl) pyridin-3-sulfonamide (100.00 mg, 275.29 μmol) was placed in a 25 ml round-bottom flask and cooled to 0 ° C, and concentrated hydrochloric acid (7 ml). Then, an aqueous solution of sodium nitrite (855.00 mg, 12.39 mmol, 1.5 ml) was added dropwise to it at 0 ° C. After completion of the dropwise addition, the mixture was warmed to room temperature, stirred for 1 h and filtered, and the filtrate was adjusted to pH 8 with saturated sodium bicarbonate solution. The resulting solution was evaporated to dryness on a rotary evaporator and then dissolved in a mixture of a solution of dichloromethane and methanol (dichloromethane: methanol = 10: 1). After stirring for 30 minutes, the resulting mixture was filtered and the filtrate was evaporated to dryness on a rotary evaporator, and the resulting crude product was purified by thin layer chromatography to obtain the title compound (30.00 mg, 28.48%). 1 H NMR (400 MHz, (Ί®01)) δ 8.76 (ά, 1 = 2.3 Hz, 1 H), 8.40 (ά, 1 = 2.5 Hz, 1 H), 2.55 (δ, 3 H), 2.17 (δ, 3 H) .

ί) 2-Methoxy-5-bromo-No (2,4-dimethylthiazol-5-yl) pyridin-3-sulfonamide.

A solution of 2-chloro-5-bromo-no. (2,4-dimethylthiazol-5-yl) pyridin-3-sulfonamide (30.00 mg, 78.39 μmol) and sodium methoxide (10.00 mg, 185.19 μmol) in methanol was placed in a sealed container a microwave tube, heated to 110 ° C and stirred for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and saturated sodium bicarbonate solution (5 ml) was added to it. The resulting mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness on a rotary evaporator to give the title compound (20.00 mg, 67.45%).

^! H NMR (400 MHz, (Ό _; 0Ι)) δ 8.24 (ά, 1 = 2.5 Hz, 1Н), 8.10 (ά, 1 = 2.5 Hz, 1Н), 3.97 (δ, 3Н), 2.44 (δ, 3Н) 2.06 (δ, 3H).

d) (3 - (2-Morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) boronic acid.

Solution of 7-bromo-3- (2-morpholinoethoxy) -4H-4-oxopyrido [1,2-a] pyrimidine (80.00 mg, 225.86 μmol), bis (pinacolato) diborone (172.06 mg, 677.58 μmol), 1.1 'bis (diphenylphosphino) ferrocene palladium chloride (49.58 mg, 67.76 μmol) and potassium acetate (66.50 mg, 677.58 μmol) in dioxane (3 ml) were placed in a 50 ml round-bottomed one-necked flask, heated to 80 ° C and stirred for 1 h in a protective atmosphere of nitrogen. After completion of the reaction, water (5 ml) was added thereto, and the mixture was extracted with ethyl acetate three times. The aqueous phase was evaporated to dryness on a rotary evaporator, and the resulting crude product was suspended with a mixture of a solution of dichloromethane and methanol (dichloromethane: methanol = 20: 1) and filtered to obtain the title compound (60.00 mg, 83.24%).

^! H NMR (400 MHz, (Ό _; 0Ι)) δ 9.00 (Lt δ., 1H), 8.23 (δ, 1H), 8.00 (ά, 1 = 7.8 Hz, 1H), 7.53 (ά, 1 = 8.3 Hz , 1H), 4.31 (bg. Δ., 4H), 3.73 (bg. Δ., 2H), 2.87 (bg. Δ., 4H), 2.65 (bg. Δ., 4H), 1.22 (δ, 4H) .

B) No. (2,4-Dimethylthiazol-5-yl) -2-methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-4H-pyrido [1,2-a] pyrimidin-7- il) pyridin-3-sulfonamide.

- 45 032642

2-Methoxy-5-bromo-No- (2,4-dimethylthiazol-5-yl) pyridin-3-sulfonamide (20.00 mg, 52.87 μmol), (3 (2-morpholinoethoxy) -4-oxo-4H-pyrido [ 1,2-a] pyrimidin-7-yl) boronic acid (60.00 mg, 188.02 μmol), 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (3.87 mg, 5.29 μmol) and potassium carbonate (21.92 mg, 158.61 μmol ) was dissolved in dioxane (3 ml) and water (0.3 ml). The reaction solution was heated to 80 ° C and stirred for 1 hour in a protective atmosphere of nitrogen. After completion of the reaction, the solution was evaporated to dryness on a rotary evaporator, and the resulting crude product was purified using preparative high performance liquid chromatography to obtain the title compound (5.00 mg, 16.51%).

² H NMR (400 MHz, SPeOP) δ 9.14 (8, 1 H), 8.64 (8, 1 H), 8.39 (b, 1 = 2.5 Hz, 1 H), 8.26 (8, 1 H), 8.03 (b, 1 = 11.3 Hz, 1H), 7.74 (b, 1 = 9.3 Hz, 1H), 4.35 (ί, 1 = 5.4 Hz, 2H), 4.10 (8, 3H), 3.76-3.69 (t, 4H), 2.88 (ί, 1 = 5.5 Hz, 2H), 2.66 (Lt. 8, 4H), 2.44 (8, 3H), 2.11 (8, 3n); M8 (Ε8Ι) t / ζ: 573 (M + H ⁺ ).

Reaction conditions: a) carbonyldiimidazole, acetonitrile, heating; B) 4- (2-chloroethyl) morpholine, cesium carbonate, dimethyl sulfoxide, heating; c) 2,4-difluoro-N- (2-methoxy-5- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide, [1,1 'bis (diphenylphosphino) ferrocene] palladium chloride, potassium carbonate, dioxane, water, heating.

Example 59. 2,4-Difluoro-No.- (2-methoxy-5- (2- (2-morpholinoethyl) -3-oxo-2,3-dihydro [1,2,4] triazolo [4,3- a] pyridin-6-yl) pyrimidin-3-yl) benzenesulfonamide

a) 6-Bromo- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one.

5- Bromo-2-hydrazono-1,2-dihydropyridine (5.00 g, 26.59 mmol) and acetonitrile (100 ml) were placed in a 250 ml round-bottomed one-necked flask, and then carbonyldiimidazole (4.75 g, 29.29 mmol) was added in a nitrogen protective atmosphere. The reaction solution was allowed to react at 80 ° C. for 2 hours and filtered to precipitate a solid. Then acetonitrile (20 ml) was added to purify the suspension. After filtration, the title compound (3.90 g, 68.53%) was obtained.

² H NMR (400 MHz, OM8O-b ₆ ) δ 12.63 (Lt. 8. 1H), 8.07 (8, 1H), 7.28-7.19 (t, 2H).

b) 6-Bromo-2- (2-morpholinoethyl) - [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one.

6- Bromo- [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one (1.00 g, 4.67 mmol) was dissolved in dimethyl sulfoxide (10 ml), and cesium carbonate (3.80 g, 11.68 mmol) and 4- (2-chloroethyl) morpholine (1.40 g, 9.34 mmol). The resulting solution was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered. Water (10 ml) was added to the filtrate, and then the resulting mixture was extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness on a rotary evaporator, and the crude product was separated and purified by column chromatography to obtain the title compound (500.00 mg, 32.72%).

² H NMR (400 MHz, OM8O-b ₆ ) δ 8.14 (8, 1H), 7.38-7.19 (t, 2H), 4.02 (ί, 1 = 6.5 Hz, 2H), 3.53-3.49 (t, 4H), 2.68 (ί, 1 = 6.3 Hz, 2H), 2.41 (L8, 4H).

b) 2,4-Difluoro-N- (2-methoxy-5- (2- (2-morpholinoethyl) -3-oxo-2,3-dihydro [1,2,4] triazolo [4,3-a ] pyridin-6-yl) pyrimidin-3-yl) benzenesulfonamide.

6-Bromo-2- (2-morpholinoethyl) - [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one (100.00 mg, 305.64 μmol),

2,4-difluoro-N- [2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridyl] benzenesulfonamide (130.28 mg, 305.64 μmol ), potassium carbonate (42.24 mg, 305.64 μmol) and 1,1'-bis (diphenylphosphino) ferrocene palladium chloride (223.64 mg, 305.64 μmol) were dissolved in dioxane (1.5 ml) and water (0.3 ml). The reaction solution was allowed to react at 80 ° C. for 2 hours under a protective nitrogen atmosphere. After completion of the reaction, the resulting solution was evaporated to dryness on a rotary evaporator

- 46 032642 to obtain the crude product. The crude product was purified using preparative high performance liquid chromatography to give the title compound (50.00 mg, 29.93%).

¹ H NMR (400 MHz, SBSB) δ 7.99-7.92 (t, 1H), 7.84 (δ, 1H), 7.75 (ά, 1 = 2.0 Hz, 1H), 7.60 (ά, 1 = 2.0 Hz, 1H), 7.50-7.43 (t, 1H), 7.27 (ά, 1 = 9.5 Hz, 1H), 7.08-6.95 (t, 2H), 4.18 (ΐ, 1 = 6.3 Hz, 2H), 3.88 (δ, 3H), 3.713 .64 (t, 4H), 2.88-2.83 (t, 2H), 2.58 (b. Δ., 4H).

Reaction conditions: a) ethyl format, sodium hydride, dimethoxyethane, heating; B) 5bromopyridin-2-amine, ammonium acetate, heating; c) phosphorus oxybromide, heating; ά) cesium carbonate, acetonitrile, heating; f) Boric acid (borate), 1,1'-bis (diphenylphosphino) ferrocene palladium chloride, potassium carbonate, dioxane, water, heating.

Example 60. 2-Chloro-4-fluoro-M- (2-methoxy-5- (3- (2-ethylmorpholinyl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridine -3-yl) benzenesulfonamide / ° γ ^Ν

0 = 3 = 0 A

SeaProd 60

a) (E) - (2-Oxo-dihydrofuran-3 (2H) -ilidene) sodium methoxide.

Sodium hydride (0.93 g, 23.23 mmol) was slowly added in portions to a 500 ml round bottom flask containing dimethoxyethane (96 ml). A solution of dihydrofuran-2 (3H) -one (2 g, 23.23 mmol) and ethyl formate (1.72 g, 23.23 mmol) in dimethoxyethane (12 ml) was added dropwise with stirring, and then ethanol (0.15 ml) was added. The reaction solution was stirred to start the reaction at 60 ° C. for 16 hours. The mixture was cooled to 25 ° C. and filtered, and the filter cake was washed with ethyl acetate (20 ml × 3) to obtain the title compound (2.1 g, 66%) in as a yellow-green solid.

¹ H NMR (400 MHz, B ₂ O) ppm δ 8.45-8.31 (t, 1H), 4.27 (ΐ, 2H), 2.71 (ΐ, 2H).

b) (E) -3 - (((5-Bromopyridin-2-yl) amino) methylidene) dihydrofuran-2 (3H) -one.

(E) - (2-oxo-dihydrofuran-3 (2H) -ilidene) sodium methoxide (1.42 g, 10.4 mmol), 5-bromopyridin-2amine (1.2 g, 6.94 mmol) and ammonium acetate (2.67 g, 34.68 mmol) placed in a 50 ml round-bottom flask and stirred to start the reaction at 120 ° C for 1 h. Liquid chromatography-mass spectrometry showed that the reaction was complete, and then the reaction solution was cooled to room temperature and slowly poured into ice water. The solid was precipitated and filtered. The filter cake was washed with water (20 ml x 3) to give the title compound as a crude solid. The crude solid was then suspended with petroleum ether (30 ml) to give the title compound (1.4 g, 75%) as a gray solid.

¹ H NMR (400 MHz, SBS1 ₃ ) ppm δ 8.29 (ά, 1H), 8.02 (ά, 1H), 7.74 (άά, 1H), 6.79 (ά, 1H), 4.44 (ΐ, 2H), 2.90 (άΐ , 2H).

c) 7-Bromo-3- (2-bromoethyl) -4H-pyrido [1,2-a] pyrimidin-4-one.

(E) -3 - (((5-Bromopyridin-2-yl) amino) methylidene) dihydrofuran-2 (3H) -one (1.4 g, 5.2 mmol) and phosphorus oxybromide (6.98 g, 24.35 mmol) were placed in 50 ml round bottom flask and stirred to start the reaction at 80 ° C for 1.5 hours. Liquid chromatography-mass spectrometry showed that the reaction was completed, and then the reaction solution was cooled to room temperature and slowly poured into ice water. The resulting mixture was adjusted to pH 8 and extracted with dichloromethane (20 ml x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain the title compound (1.2 g, 69%) as a yellow solid.

¹ H NMR (400 MHz, CSCE) ppm δ 9.17 (ά, 1H), 8.27 (δ, 1H), 7.74 (άά, 1H), 7.54 (ά, 1H), 3.73 (ΐ, 2H), 3.21 (ΐ, 2H).

ά) 7-Bromo-3- (2-ethylmorpholinyl) -4H-pyrido [1,2-a] pyrimidin-4-one

7-Bromo-3- (2-bromoethyl) -4H-pyrido [1,2-a] pyrimidin-4-one (0.2 g, 0.6 mmol), morpholine (78.73 mg, 0.9

47 032642 mmol) and cesium carbonate (0.59 g, 1.81 mmol) were placed in a 50 ml round-bottom flask and stirred to start the reaction at 70 ° C for 12 hours. Liquid chromatography-mass spectrometry showed that the reaction was completed and then the reaction solution was cooled to room temperature, water was added, and the resulting mixture was extracted with dichloromethane (20 ml x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude title compound as an oil, which was directly used in the next reaction.

f) 2-Chloro-4-fluoro-I- (2-methoxy-5- (3- (2-ethylmorpholinyl) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin- 3-yl) benzenesulfonamide.

7-Bromo-3- (2-ethylmorpholinyl) -4H-pyrido [1,2-a] pyrimidin-4-one (0.59 mmol) was dissolved in dioxane (2 ml) and water (0.4 ml), and 2-chlorine was added -4-fluoro-I- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide (0.59 mmol), potassium carbonate ( 1.18 mmol) and 1.1'bis (diphenylphosphino) ferrocene palladium chloride (22 mg) in a protective nitrogen atmosphere. The mixture was allowed to react at 100 ° C for 1 h under the reaction conditions of microwaves. Liquid chromatography mass spectrometry showed that the reaction is complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography and preparative high performance liquid chromatography to obtain the title compound.

1 H NMR (400 MHz, SESS) ppm δ 9.08 (δ, 1H), 8.29 (δ, 1H), 8.17 - 8.09 (t, 2H), 7.94 (ά, 1H), 7.85-7.77 (t, 1H), 7.75 -7.68 (t, 1H), 7.28 (ά, 1H), 7.18-7.12 (t, 1H), 4.00 (δ, 3H), 3.79 (Lr. Δ., 3H), 2.93 (Lr. Δ., 1H) .

The following 1 compound was also synthesized in accordance with the method of obtaining compound 1.

Compound Structure M8 (E8) [M + H] ⁺ 61 1 ο =, ν о о = | = о ^ 3 = ° - / З ^{0 ν} Α 621.7

The following 3 compounds were also synthesized in accordance with the method of obtaining Compound 7.

The following 31 compounds were also synthesized in accordance with the method for producing compound 21.

- 48 032642

Compound Structure M8 (E8) [M + H] ⁺ 65 66 67 68 69 o ΗΝ Ν V Ν η o4 = o ME o ^ ° “ф Е 1 0. -Ν С1 О _{ч /} О> 0 | _R L / ⁿ AchT O 1 01 ρ _{4 /} ρ °> ^ ^Νχ | ΐ 0 g / kf ' ⁸ N Ν _R О ⁿ kl _m Т 1 О / ° γ% о 0 = 5 = 0 MM М ^ φ- Е - ° γ% o 0 = 5 = 0 MM М ^ ^С к Μ Ε 604 606 604 604 672 70 .0. .Ν. ~ ΊΓ1 ϊ ν ο4 = ο Ι ^ Α) Ι 1 ^ 0 φ Ε 619 71 1 ΎΊ ⁰ Μ Η Ν - ^ k ^ k ^ _Ν ^ k-- ⁰ \ k \ E ο4 = ^ο ΜΜ φ Ε 589 72 ΜΑ ϊ μ < _ΗΝ ΜΜ _Ν Μ ° ^^ Μ θ4 = Ο ΜΜ фг Ε 618 73 ₀ ΗΝ Ν ιΤ ^ θ'γΛ 0 = 3 = 0 to ^ M X) Ε 547 74 ^{/ 0} Mk ° 0 = 3 = 0 E ^ · U to A. “f E 575 75 1 Ο ^ Ν 0 and AMAM ⁰ ^^ ¹ ι ι 1 0 = 3 = 0 Ah. > 1 ΝΗ fg E 590

- 49 032642

90 ⁰ 0 = 8 = 0 Υ ^τ g 632 91 χ .Ν. Υ ° 0 = 3 = 0 ΜΥ γ> γ ^τ Ε 619 92 ^ 0 Ν θ XX ί ο 0 = 8 = 0 to X. Y ^Η γ Ε 603 93 / ΟγΥΥ _{ο α} γ ° γ ° Ε 668 94 .Ο. .Ν. Υ ° ηι / 'Άλ-νΥ ^ · -, /' · / ο = Υ ΜΥ + ^ΝΗ γ Ε 604 95 '° γ ^Ν ι ⁰ ΗΝ _Ν Α + Υγ ЖЗЕ ₃ 0 = 8 = 0 Υ X Y to γ - Ε 661

The following 2 compounds were also synthesized in accordance with the method of obtaining compound 45.

- 51 032642

Reaction conditions: a) 2-bromo-1,1-diethoxyethane, potassium carbonate, heating; B) concentrated hydrochloric acid, heating; c) triethylorthoformate, 2,2-dimethyl-1,3-dioxane-4,6-dione, heating; EUN, heating; ά) diphenyl ether, heating under reflux; e) concentrated sulfuric acid, nitric acid; ί) powdered Fe, ammonium chloride, ethanol, water, heating; e) 3-amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one, dichloromethane, 4A molecular sieve powder, acetic acid, sodium triacetoxyborohydride; I) 2-chloro-4-fluoroA- (2-methoxy-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) benzenesulfonamide, dioxane, [ 1,1'bis (diphenylphosphino) ferrocene] palladium chloride, potassium carbonate, water, heating.

Example 98. 2-Chloro-4-fluoro-N- (2-methoxy-5- (3 - ((2-morpholinoethyl) amino) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7- il) pyridin-3-yl) benzenesulfonamide

a) 4- (2,2-Diethoxyethyl) morpholine.

Morpholine (2.21 g, 25.37 mmol, 1.00 equiv.) And 2-bromo-1,1-diethoxy-ethane (5.00 g, 25.37 mmol, 1.00 equiv.) Were placed in a three-necked round-bottom flask, potassium carbonate (7.01 g, 50.73 mmol) was added. , 2.00 equiv.), And the mixture was stirred at 80 ° C for 2 hours. The reaction mixture was cooled to room temperature, and 20 ml of water was added. The mixture was extracted with dichloromethane (20 ml X 2), dried over anhydrous sodium sulfate and concentrated to obtain the title compound (3.50 g, 67.87%) as a yellow oil. The crude product was directly used in the next reaction.

¹ H NMR (400 MHz, СОС1 ₃ ) δ 4.62-4.65 (t, 1 N), 4.61 (8, 1Н), 3.66 (ΐ, 1 = 4.6 Hz, 4Н), 3.45-3.59 (t, 3Н), 3.33 (ά, 1 = 5.6 Hz, 2Н), 2.49 (ά, 1 = 5.1 Hz, 4Н), 1.19-1.22 (t, 5Н), 1.18 (8, 2Н).

b) 2-Morpholinoacetaldehyde.

4- (2,2-Diethoxyethyl) morpholine (800.00 mg, 3.94 mmol, 1.00 eq.), Dissolved in concentrated hydrochloric acid (4 ml), was placed in a three-necked round-bottom flask. The mixture was stirred at 80 ° C for 3 hours. The mixture was cooled to room temperature, adjusted to pH 10 with saturated aqueous sodium bicarbonate, and extracted with ESM dichloromethane (50 ml X 3), dried over anhydrous sodium sulfate and concentrated to obtain the title compound (350.00 mg, 67.87%) as colorless oils. The crude product was directly used in the next reaction.

¹ H NMR (400 MHz, СОС1 ₃ ) δ 9.69 (8, 1 Н), 3.62-3.67 (t, 4Н), 3.18 (8, 2Н), 2.54-2.60 (t, 4Н).

c) (E) -5 - (((5-Bromopyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxan-4,6-dione Triethylorthoformate (25.8 g, 0.174 mol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (25.1 g, 0.174 mol) was placed in a three-necked round-bottom flask and stirred to start the reaction at 60 ° C for 2 hours. A solution was added dropwise to the above mixture. 2-amino-5-bromopyridine (30 g, 0.174 mol) in ethanol (150 ml). The reaction solution was stirred to start the reaction at 60 ° C for 2 hours. The resulting mixture was cooled to 25 ° C and filtered, and the filter cake was washed with ethanol (200 ml X 3) to obtain the title compound (40 g, 70 %) as a white solid.

¹ H NMR (400 MHz, COC1 ₃ ) δ 1.77 (8, 6H), 6.93-7.04 (t, 1H), 8.44-8.53 (t, 1H), 7.85-7.91 (t, 1H), 9.319.42 (t , 1H), 11.28-11.40 (t, 1H).

ά) 7-Bromo-4H-pyrido [1,2-a] pyrimidin-4-one.

(E) -5 - (((5-Bromopyridin-2-yl) imino) methyl) -2,2-dimethyl-1,3-dioxan-4,6-dione (18 g, 0.056 mmol) and diphenyl ether ( 180 ml) was placed in a 250 ml round-bottom flask and stirred to start the reaction at 220 ° C for 1 h. TGS showed that the reaction was completed, and then the reaction solution was cooled to room temperature and purified by silica gel column chromatography to obtain the the title compound (10 g, 80%).

¹ H NMR (400 MHz, СОС1 ₃ ) δ 6.46 (ά, 1Н), 7.53 (ά, 1Н), 7.75 (άά, 1Н), 8.27 (ά, 1Н), 9.19 (ά, 1Н).

e) 7-Bromo-3-nitro-4H-pyrido [1,2-a] pyrimidin-4-one.

7-Bromo-4H-pyrido [1,2-a] pyrimidin-4-one (5 g, 22.2 mmol) was placed in a 100 ml three-necked round-bottom flask, concentrated sulfuric acid (11.2 ml) was added and nitric acid (5.2) was added dropwise. ml) at 5-10 ° C. The reaction proceeded at 20 ° С for 3 h. The reaction solution was slowly poured into ice water, adjusted to pH 8 with 1N. sodium hydroxide and filtered. The filter cake was collected and evaporated to dryness on a rotary evaporator under reduced pressure to give a yellow title product (4.0 g, 66.7%).

¹ H NMR (400 MHz, СОС1 ₃ ) δ 9.47 (ά, 1Н), 9.35 (8, 1Н), 8.14 (άά, 1Н), 7.81 (ά, 1Н).

ί) 3-amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one.

7-Bromo-3-nitro-4H-pyrido [1,2-a] pyrimidin-4-one (4.0 g, 14.7 mmol, 1.0 equiv.) And ammonium chloride

- 52 032642 (11.8 g, 220.54 mmol, 15.0 equiv.) Were placed in a 250 ml round bottom flask, and ethanol (50 ml) and water (10 ml) were added. Powdered iron (1.32 g, 220.54 mmol, 15.0 equiv.) Was added portionwise at room temperature. The mixture was placed in an oil bath at 70 ° C and stirred to start the reaction for 12 hours. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with dichloromethane (50 ml). The organic phases were combined and washed with water (30 ml x 2) and saturated brine (30 ml x 2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product (3.29 g, 93%) as a yellow solid.

¹ Η NMR (400 MHz, GHS,) δ 4.13 (L8, 2Η) 7.39 (ά, 1 = 0.98 Hz, 2 Η) 7.96 (8, 1 Η) 9.00 (8, 1 Η).

d) 7-Bromo-3 - ((2-morpholinoethyl) amino) -4H-pyrido [1,2-a] pyrimidin-4-one.

2-Morpholinoacetaldehyde (80.70 mg, 624.84 μmol, 3.00 eq.) And 3-amino-7-bromo-4H-pyrido [1,2-a] pyrimidin-4-one (50.00 mg, 208.28 μmol, 1.00 eq.), dissolved in dichloromethane (5 ml) was placed in a three-necked round-bottom flask. A 4A powder molecular sieve was added and the reaction mixture was stirred at 25 ° C for 1 h. Acetic acid (15.01 mg, 249.94 μmol, 1.20 equiv.) And sodium triacetoxyborohydride (52.97 mg, 249.94 μmol, 1.20 equiv.) Were added, and the resulting as a result, the mixture was stirred at 25 ° C for 1 h. The color of the reaction solution changed from yellow to red. The reaction was stopped with 0.5 ml of methanol, and the reaction mixture was filtered. The filter cake was washed with 10 ml of dichloromethane, and the filtrate was concentrated and purified using preparative silica gel chromatography plate to give the title compound (32.00 mg, 43.50%) as a brown solid.

I) 2-Chloro-4-fluoro-P- (2-methoxy-5- (3 - ((2-morpholinoethyl) amino) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl ) pyridin-3-yl) benzenesulfonamide.

7-Bromo-3 - ((2-morpholinoethyl) amino) -4H-pyrido [1,2-a] pyrimidin-4-one (40.00 mg, 90.60 μmol, 1.00 equiv.) And 2-chloro-4-fluoro- P- (2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3yl) benzenesulfonamide (48.13 mg, 108.72 μmol, 1.20 equiv.), Dissolved in dioxane (3 ml), was placed in a three-necked round-bottom flask. [1,1'-Bis (diphenylphosphino) ferrocene] palladium chloride (3.31 mg, 4.53 μmol, 0.05 equiv.), Potassium carbonate (37.56 mg, 271.79 μmol, 3.00 equiv.) And water (1 ml) were added. The mixture was stirred at 80 ° C. for 2 hours under a protective nitrogen atmosphere. Liquid chromatography mass spectrometry showed that the reaction is complete. The reaction solution was filtered and concentrated to obtain a crude product. The crude product was separated using preparative liquid chromatography to obtain the title compound (5.70 mg, 10.25%) as a white solid.

'' And NMR (400 MHz, CEC) δ 8.83 (8, 1 Η), 8.06-8.15 (t, 2Η), 7.90 (ά, 1 = 2.2 Hz, 1 Η), 7.71 (8, 1 Η), 7.54 ( ά, 1 = 9.3 Hz, 1 Η), 7.38 (άά, 1 = 9.4, 1.8 Hz, 1 Η), 7.26 (ά, 1 = 2.4 Hz, 1 Η), 7.09-7.17 (t, 1 Η), 5.17 (Bg. 8., 1 Η), 3.97 (8, 3Η), 3.74 (ΐ, 1 = 4.4 Hz, 4 Η), 3.29 (ά, 1 = 5.4 Hz, 2 Η), 2.72 (ΐ, 1 = 5.9 Hz, 2 Η), 2.51 (Lt. 8, 4 Η).

Reaction conditions: a) Raney nickel, tetrahydrofuran, tert-butoxy formic anhydride, hydrogen, heating; B) 7-bromo-3- (2-morpholinoethoxy) pyrido [1,2-a] pyrimidin-4-one, dioxane, potassium carbonate, water, [1,1'-bis (diphenylphosphino) ferrocene] palladium chloride, heating ; c) dichloromethane, a solution of dioxane hydrochloride; ά) 2-chloro-4-fluoro-benzenesulfonyl chloride, pyridine.

Example 99. 2-Chloro-4-fluoro-No ((2-methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridine -3-yl) methyl) benzenesulfonamide

Soshproschl 99) 9

a) tert-Butyl ((2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) methyl) carboxamide.

Raney Nickel (9.88 mg, 115.34 μmol) was added to a one-necked round-bottom flask filled with nitrogen. Tetrahydrofuran (10.00 ml), 2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyridin-3-cyano (150.00 mg, 576.70 μmol) and tert-butoxy formic acid were added. anhydride (151.04 mg, 692.04

- 53 032642 μmol). The mixture was stirred at 80 ° С for 2 h under a hydrogen pressure of 40 ρδί. LC / MS showed that the reaction is complete. The reaction mixture was filtered through celite, and the filtrate was evaporated to dryness on a rotary evaporator to give the yellow title compound (200.00 mg, 69.50%), which was directly used in the next reaction.

b) tert-Butyl ((2-methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) methyl) carboxamide.

tert-Butyl ((2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-yl) methyl) carboxamide (200.00 mg, 400.83 μmol) and 7-bromo-3- (2-morpholinoethoxy) pyrido [1,2-a] pyrimidin-4-one (141.98 mg, 400.83 μmol) was dissolved in dioxane (10.00 ml), and a solution of potassium carbonate (110.80 mg, 801.67) was added. μmol) in water (3.00 ml). [1,1'-Bis (diphenylphosphino) ferrocene] palladium chloride (14.66 mg, 20.04 μmol) was added. The mixture was stirred at 80 ° C. for 2 hours under a protective nitrogen atmosphere. LC / MS showed that the reaction is complete. The reaction solution was concentrated, washed with 5 ml of water and purified with ρ-TLC (dichloromethane: methanol = 20: 1) to give the yellow title compound (100.00 mg, 46.33%).

¹ H NMR (400 MHz, SES1 ₃ ) δ 9.11 (δ, 1H), 8.35 (ά, 1 = 2.0 Hz, 1 H), 8.17 (δ, 1H), 7.74-7.83 (t, 2H), 7.647.71 (t, 1 H), 4.32 (t, 1 = 5.5 Hz, 4 H), 4.04 (δ, 3 H), 3.73-3.76 (t, 4 H), 2.85-2.89 (t, 2 H), 2.62 (L δ. , 4H), 1.45 (δ, 9 N).

c) 7- (5- (Aminomethyl) -6-methoxypyridin-3-yl) -3- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-4-one.

tert-Butyl ((2-methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7-yl) pyridin-3-yl) methyl) carboxamide ( 80.00 mg, 148.56 μmol) was dissolved in dichloromethane (10.00 ml), and a solution of dioxane hydrochloride (4 M, 2.00 ml) was added dropwise at 0 ° C. The mixture was warmed to room temperature (25 ° C) and stirred for 1 h. LC / MS showed that the reaction was complete. Potassium carbonate (1.12 g) was added and the resulting mixture was stirred for 30 minutes and filtered, the filter cake was washed with dichloromethane (10 ml) and the filtrate was evaporated to dryness on a rotary evaporator to obtain the title compound (70.00 mg) as yellow crude product that was directly used in the next reaction.

ά) 2-Chloro-4-fluoro-B - ((2-methoxy-5- (3- (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-7yl) pyridin-3 -yl) methyl) benzenesulfonamide.

7- (5- (Aminomethyl) -6-methoxypyridin-3-yl) -3 - (2-morpholinoethoxy) -4-oxo-4H-pyrido [1,2-a] pyrimidin-4-one (70.00 mg, 119.09 μmol) was dissolved in pyridine (3.00 ml), and 2-chloro-4-fluoro-benzenesulfonyl chloride (30.01 mg, 131.00 μmol) was added dropwise. The mixture was stirred at 25 ° C. for 1 h. LC / MS showed that the reaction was complete. The reaction solution was concentrated and purified using ρ-TLC (dichloromethane: methanol = 10: 1) and recrystallized from methanol (3 ml) to obtain the title compound (26.00 mg, 36.14%) as a white solid.

Ίί NMR (400 MHz, SIS1 ₃ ) δ 8.95 (δ, 1Н), 8.26 (ά, 1 = 2.5 Hz, 1 Н), 8.19 (δ, 1Н), 8.02 (άά, 1 = 8.3, 5.8 Hz, 1 Н ), 7.62-7.72 (t, 2H), 7.46 (ά, 1 = 2.0 Hz, 1 N), 7.01-7.11 (t, 2H), 5.87 (ΐ, 1 = 6.5 Hz, 1 N), 4.34 (ΐ, 1 = 5.5 Hz, 2H), 4.25 (ά, 1 = 6.5 Hz, 2H), 4.02 (δ, 3H), 3.75 (ΐ, 1 = 4.5 Hz, 4H), 2.89 (ΐ, 1 = 5.5 Hz, 2H) 2.63 (Lt. Δ., 4H).

Experimental example 1. The study of the activity of the enzyme Ιη νίΐτο.

ΡΙ3Κ (ρ110α) the kinase activity of the compounds in all examples of the present invention was investigated using the following two methods, respectively.

Method Ι.

Reaction buffer: HEPE8 50 mM (pH 7.0), Chai ₃ 0.02%, V8L 0.01%, orthovanadate 0.1 mM and 1% ΌΜ 8Θ.

Detection buffer: HEPE8 10 mM (pH 7.0), V8L 0.02%, KB 0.16 M and EITL 4 mM.

Enzymes for the reaction: recombinant full-sized human P13K ρ110α subunit (molecular weight = 128.4 kDa) histidine-labeled at the Ν-end and unlabeled p85a subunit (molecular weight = 83.6 kDa), which were expressed in insect cells.

Substrate for the reaction: 10 μM P1P2 substrate (P1 (4.5) P2).

Reaction conditions: 10 μM P1 (4,5) P2 and 10 μM ATP.

Reaction steps include:

1) preparation of the substrate in a freshly prepared reaction buffer;

2) adding kinase to the reaction solution of the substrate and gentle mixing;

3) transfer of the compound dissolved in 100% ΌΜ8Θ to the kinase reaction solution using the acoustic method (Ec1ю550; nanolitre range) and incubation at room temperature for 10 min;

4) adding ATP of the appropriate concentration to the reaction system;

5) incubation at 30 ° C for half an hour;

6) completion of the reaction by adding a stop solution;

7) adding a detection buffer and incubation overnight; and

8) detection using a method of homogeneous fluorescence with time resolution

- 54 032642 (NTBE) (excitation wavelength 320 nm, measuring the ratio of the readings of the radiation wavelength at 615 nm and 665 nm).

Method II.

Analysis Method ΛΌΡ-Θίο.

Dilution of the compound: the test compound was diluted with a 3-fold concentration gradient, and a total of 10 concentrations were obtained (from 10,000 nM to 0.5 nM).

Research Methodology.

nl of the compound was transferred to a reaction plate (RegktE1teg # 6007299) and 3 μl of an enzyme / substrate mixture (0.33 nM P13Ka1rya, MShroge # 14-602-K / 166.5 μM ΡΙΡ2) was added. After 20 minutes of incubation, 2 μl of ATP solution (100 μM) was added to initiate the reaction. After the reaction was carried out for 2 hours at room temperature, 5 μl of ΑΌΡ-Θ1ο reagent was added to complete the kinase reaction. The mixture was then incubated at room temperature for 60 minutes to completely deplete the remaining unreacted ATP. 10 μl of kinase detection reagent was added, and after 40 min of incubation at room temperature, fluorescence was read on an ΕηνΪ8ΐοη instrument. ΡΙΡ2, ATP, ΑΌΡ-Θ1ο, and the kinase detection reagent were all obtained from the kit for measuring ATP by the kinase activity of ΑΌΡ-Θ1ο ^ gote ^ a # Y 1792).

Analysis of the data.

1C _{50 was} calculated using the standard 4-parameter method (Μοάе1205, ХЬ-ίϊΙ, 1ΌΒ8).

tTOV kinase activity of the compounds in all examples of the present invention was investigated using the following methods.

Reaction buffer: 20 mM Nere8 (pH 7.5), 10 mM MdS1 _2, 2 mM MpS1 _2, 1 mM ΕΘΤΑ, 0.02% Vgts35, 0.02 mg / ml Β8Α, 0.1 mM ^ ^ UO 2 mM ΌΤΤ EM8O and 2%.

Enzyme for the reaction: recombinant human tTOV fragment (amino acid 1360-2549, molecular weight = 163.9 kDa) O8T-labeled at the конце-end, which was expressed in insect cells.

The substrate for the reaction: recombinant full-sized human 4EVP1 (molecular weight = 13.6 kDa) histidine-labeled at the конце-end, which was expressed in bacteria.

Reaction conditions: 3 μM 4EVP1 and 10 μM ATP. Reaction steps include:

1) adding a reaction substrate and other reaction agents to a freshly prepared reaction buffer;

2) adding kinase to the reaction solution of the substrate and gentle mixing;

3) transfer of the compound dissolved in 100% EM8O to the kinase reaction solution using the acoustic method (ΕΛο550; nanoliter range), and incubation at room temperature for 20 minutes;

4) adding ³² P-ATP of the appropriate concentration to the reaction system;

5) incubation at room temperature for 2 hours;

6) detection of kinase activity using the binding method on P81 filters.

The results of the study are shown in table. 3 below.

Table 3. The results of the study of enzyme activity ΐη νίίτο

Compound ΡΙ3Κ (ρ110α) enzymatic activity! C50 one BUT 2 BUT 3 BUT four BUT five BUT 6 BUT 7 BUT eight BUT 9 BUT ten BUT eleven BUT 12 BUT 13 BUT 14 BUT 15 BUT sixteen BUT 20 BUT 21 BUT 22 BUT

TTOK enzymatic activity_1С5о Research Method ΡΙ3Κ WITH Method I WITH Method I ϋ Method I ΝΤ Method II ΝΤ Method II ϋ Method I ϋ Method I ϋ Method I ABOUT Method I ϋ Method I ϋ Method I WITH Method I ϋ Method I ϋ Method I WITH Method I WITH Method I WITH Method I ΝΤ Method II ΝΤ Method II

- 55 032642

23 BUT ΝΤ Method II 25 BUT ϋ Method II 27 BUT WITH Method II 32 BUT with Method II 33 BUT ΝΤ Method II 34 BUT ΝΤ Method II 35 BUT WITH Method I 36 BUT ϋ Method I 37 BUT with Method I 38 AT ΝΤ Method II 39 AT ΝΤ Method II 40 AT ΝΤ Method II 41 at ϋ Method I 42 BUT ϋ Method I 43 BUT ϋ Method I 44 BUT ϋ Method I 51 AT ΝΤ Method II 52 AT ΝΤ Method II 54 ϋ ΝΤ Method II 56 ϋ ΝΤ Method II 58 ϋ ΝΤ Method II 61 BUT ΝΤ Method II 62 BUT ΝΤ Method II 63 BUT ΝΤ Method II 64 BUT ΝΤ Method II 65 BUT ΝΤ Method II 66 AT ΝΤ Method II 67 AT ΝΤ Method II 68 BUT ΝΤ Method II 70 AT ΝΤ Method II 71 AT ΝΤ Method II 73 AT ΝΤ Method II 74 at ΝΤ Method II 75 BUT ΝΤ Method II 77 AT ΝΤ Method II

78 AT ΝΤ Method II 79 BUT ΝΤ Method II 80 BUT ΝΤ Method II 81 BUT ΝΤ Method II 82 BUT ΝΤ Method II 83 AT ΝΤ Method II 84 AT ΝΤ Method II 85 AT ΝΤ Method II 86 BUT ΝΤ Method II 87 BUT ΝΤ Method II 88 BUT ΝΤ Method II 89 BUT ΝΤ Method II 90 BUT ΝΤ Method II 92 BUT ΝΤ Method II 93 BUT ΝΤ Method II 95 AT ΝΤ Method II

Note: A <1 nM; 1 nM <B <50 nM; 50 nM <C <200 nM; 200 nM <Ό; and NT stands for not tested.

Experimental example 2. The study of cellular activity Ιη Uygo.

The stages of the experiment and procedure include:

1) MSV-7 cells were seeded at a concentration of 2.5000 cells per well in a 96-well plate for

- 56 032642 tissue cultures in a complete medium containing 10% ΕΒ8;

2) on the second day, the medium was removed from the wells, and the cells were treated with compounds at a specific concentration (for primary screening) or serial dilutions (to determine 1C ₅₀ ) in serum-free medium for 2 hours;

3) the cells were treated with 10 μg / ml insulin in serum-free medium for 30 min;

4. During the waiting period, a lysis solution was prepared as shown below:

a) the enhancer must be removed from the refrigerator to defrost;

b) a concentrated lyse solution was obtained by 10-fold dilution of the enhancer in a 5x lysis buffer;

c) a lyse solution was obtained by 5-fold dilution of the concentrated lyse solution άά ^ Ο;

5) all media were removed from the wells, and the wells were quickly washed with ΡΒ8 once;

6) 50 μl of a freshly prepared lyse solution was added to each well with stirring at room temperature for 10 minutes;

7) after confirmation that all cells are separated from the wells, the lysing solution along with cell debris was transferred to 1.5 ml tubes;

8) the contents of the tubes were mixed several times on a vortex to thoroughly mix the lyse solution and cells, and then the mixture was centrifuged at 12,000 d for 10 min at 4Ό;

9) The desired number of strips of the E1 §L-Ope microplate was determined, unused strips were removed from the frame and returned to the storage case and closed, the wells for use in the analysis were washed with 200 μl άά ^ Ο to remove the preservative before use;

10) 50 μl of an antibody mixture solution was added to each well (an antibody mixture solution was obtained by mixing the immobilized antibody reagents and the detection antibody in equal proportions, avoiding vigorous stirring);

11) 25 μl of lysate was added to each well of the EIBL-Oe microplate, the microplate was closed with an adhesive film and incubated for 1 h at room temperature on a microplate shaker.

12) each well was washed 3 times with 150 μl of 1x washing buffer, after the last washing, all remaining washing buffer was removed from the wells, if necessary, leave the microplate in 1x washing buffer for 30 minutes until a solution of the substrate mixture was prepared;

13) a substrate mixture solution must be prepared before use, 100 μl of the substrate mixture solution was added to each well, and then the microplate was sealed with foil and incubated at room temperature for 10 minutes on a microplate shaker;

14) 10 μl of stop solution was added to each well and then lightly mixed (5-10 s) on a microplate shaker;

15) the appropriate EFL-Opera filter set was installed to read the fluorescence intensity signal.

The results of the study are shown in table. 4 below.

- 57 032642

Table 4. The results of the study of cellular activity

Compound Cell activity one BUT

2 BUT 3 ϋ four AT five ϋ 7 BUT eight AT 9 WITH ten AT AND BUT 12 ϋ 14 BUT 15 BUT sixteen WITH 20 BUT 21 BUT 22 WITH 23 AT 25 BUT 27 AT 28 BUT 29th ϋ thirty ϋ 32 AT 33 ϋ 34 AT 35 BUT 36 BUT 37 WITH 42 WITH 43 AT 62 with 63 BUT 65 BUT

Note: A <50 nM; 50 nM <B <100 nM; 100 nM <C <250 nM; and Ό> 250 nM.

- 58 032642

Conclusion: the compounds of the present invention have a significant inhibitory effect on ΡΙ3Κ, but a weak inhibitory effect on tTOV.

Pharmacodynamic experiment Ιη νινο.

Studies have been conducted to determine whether the test drugs have the efficacy of νη νινο in relation to human colon cancer CO-04-0032 in an experimental animal model and in relation to stomach cancer 8T-02-0013 in an experimental animal model. Animal nutrition, feed composition, experimental observation, experimental indicators, as well as the end of the experiment and analysis of these experiments were described as follows: Animal nutrition: Animals should be fed in the experimental environment for 3-7 days before the experiment. Animals were caged (5 per cage) in a room for keeping animals of class 8ΡΕ with 1US (independent ventilation system). Cells, bedding and drinking water - everything must be sterilized before use, and sterilization and disinfection data are given in the appendix. All laboratory personnel should wear protective clothing and latex gloves when working in the animal welfare room. The information card of each cell should indicate the number, gender, strain, date of receipt, dosage, experiment number, group and start date of the experiment for the animal in the cell. Cells, feed and drinking water were replaced twice a week. The feeding environment and lighting conditions were as follows:

temperature: 20-26 ° C;

humidity: 40-70%;

light cycle: 12 hours of light, 12 hours of darkness.

Feed composition: The feed met the requirements of the standards for identification of feed for experimental animals. The maximum content of contaminants was in the controlled range, and the manufacturer was responsible for the scheduled inspection. Drinking water was autoclaved.

Distribution of animals into groups: animals were weighed and tumor volume was measured prior to dosing. Animals were randomly grouped according to the volume of their tumors (randomized block scheme).

Observation: the experimental program and any changes were carried out after the approval of δ1ι; · ιη§1ι; · ιί νιιχί ArrTes Co., Yb. Institutional Committee for Animal Care and Use (1ACIS). The use and quality of life of experimental animals was carried out in accordance with the rules of the International Association for the Certification and Accreditation of the content of laboratory animals (AAABAC). Animal health and mortality were monitored daily, and routine examinations included observation of the effects of tumor growth and drug therapy on daily animal behavior, such as activity, food and water consumption, changes in body weight (weight was measured twice a week), signs or other abnormal conditions. The number of dead animals and side effects were recorded based on the number of animals in each group, and the corresponding entries are shown in the appendix.

Experimental indicators: experimental indicators were used to study whether tumor growth is inhibited or slows down, or whether the tumor is cured. Tumor diameter was measured twice a week using a caliper. Tumor volume was calculated as: V = 0.5a x b ² , where a and b denote the long and short diameter of the tumor, respectively. Tumor growth inhibition (TC1) by compound was evaluated using T-C (days) and T / C (%). T-C (days) reflects an indicator of tumor growth retardation, where T is the average number of days for a tumor in the administration group to reach a predetermined volume (e.g. 1000 mm ³ ), and C is the average number of days for a tumor in the control group to reach the same volume. T / C (%) reflects the rate of inhibition of tumor growth, where T and C, respectively, represent the mass of the tumor (tumor volume) in the administration group and in the control group on that day.

The degree of inhibition of tumor growth was calculated as: TC1 (%) = [1- (Τί-Τ0) / (νί-ν0)] χ100, where T1 represents the average volume of the tumor in this group of administration on a specific day, T0 represents the average volume of the tumor in the administration group immediately before the dose; V represents the average tumor volume in the control group receiving the carrier on a particular day (on the same day as T1); and ν0 represents the average tumor volume in the control group receiving the carrier immediately before the dose. After the experiment was completed, the tumor was weighed and the T / C ratio was calculated. T and C respectively represent the weight of the tumor in the administration group of the drug and in the control group receiving the carrier.

End of the experiment: the animal will be euthanized if its health continues to deteriorate, or the tumor volume exceeds 2000 mm ³ , or there is a serious disorder or pain. An animal will be euthanized by a veterinarian if it exhibits any of the following conditions:

significant weight loss of more than 20%;

cannot eat and drink water freely;

the average tumor volume in the control group was 2000 mm ³ and the experiment was terminated;

- 59 032642 the animal has the following clinical manifestations, and the condition continues to deteriorate: standing on end of fur;

curved back;

eyes, nose, ears or legs become pale;

dyspnea;

convulsions;

persistent diarrhea;

dehydration;

slow motion;

making sounds.

Data analysis: comparisons between three or more groups were performed using одноνΑ univariate analysis of variance. If the values of Γ differed significantly, multiple comparisons should be made after the analysis of ΑΝΟνΑ. All data analysis was performed using 8P88 17.0 software. The value of p <0.05 was considered as a significant difference.

Pharmacodynamic studies of ίη νίνο of the test drug in a model of the subcutaneous tumor xenograft of human colon cancer CO-04-0032.

The scheme of the experiment.

Creating a model of a transplant tumor of human origin: a model of human colon cancer CO-04-0032 was originally obtained from tumor samples resected during surgery. Samples were collected and used strictly in accordance with the ethical laws and regulations of the citizen, hospital and company, including the informed consent of the patient. The model creation procedure was carried out strictly in accordance with the company's internal 8OP. Transfer rules include: a nude mouse after inoculation of a tumor sample was designated as generation P0; one next transfer was designated as generation P1, and so on; the resuscitated sample was named as GR. The tumor tissue used in this experiment was the generation of GR4.

Animals: ΒΑΕΒ / s nude mice, females, age 6-8 weeks, weight: 18-20 g; obtained from 8EapgLa1 81rrg / BK LaGaFGu Λιιίιιιαΐ Co., ITC1.

Tumor inoculation: CO-04-0032 tumor mass with a volume of about 30 mm ^{3 was} inoculated subcutaneously on the right rear of each mouse. Group classification and administration were started when the average tumor volume reached about 100-200 mm ³ .

Pharmacodynamic study results: see FIG. 1-1, 1-2a and 1-2b.

Pharmacodynamic studies of ΐπ νίνο of the test drug in a model of the subcutaneous tumor xenograft of human gastric cancer 8T-02-0013.

The scheme of the experiment.

Creating a model of a transplant tumor of human origin: POX model 8T-02-0013 was originally obtained from clinical specimens resected during surgery. A nude mouse after implantation was designated as the P0 generation; the next generation of P0 was designated as the generation of P1, with subsequent generations of successive grafts in mice, and so on. The generation of the tumor of GR2 was resuscitated to obtain the generation of the tumor of GR3. The generation of the GR3 tumor was passed on to the generation of the GR4 tumor, which was used in this study.

Animals: ΒΑΕΒ / s nude mice, females, age 6-8 weeks, weight: 18-20 g; obtained from 8ΙιηπμΙΐίΐί 8 ^ pp ^ / ΒK RaBopPogu Λπίιιιηη Co., Rad.

Tumor inoculation: 8T-02-0013 tumor tissue of generation GR4 with a volume of about 30 mm ^{3 was} inoculated subcutaneously on the right rear of each mouse. Group classification and administration were started when the average tumor volume reached about 150-200 mm ³ .

Pharmacodynamic study results: see FIG. 2-1 and 2-2.

Claims (10)

CLAIM 1. The compound represented by formula (I), or its pharmaceutically acceptable salt (^ 1) 1T11 (I) where E is selected from the group consisting of C1-6 alkyl, from 3 to 10 membered aryl, from 3 to 10 -membered cycloalkyl and from 3 to 10 membered heteroaryl, wherein said C1-6 alkyl, from 3 to 10 membered aryl, from - 60 032642 3- to 10-membered cycloalkyl or 3- to 10-membered heteroaryl are optionally substituted with 1, 2 or 3 K ₃ , and K _{3 is} selected from the group consisting of Η, E, C1, Br, I, ΝΗ ₂ and C _{1 -10} alkyl, wherein said 3- to 10-membered heteroaryl contains 1, 2, or 3 heteroatoms, each of which is independently selected from the group consisting of Ν, O, and 8; one of E and 0 is selected from the group consisting of -C (= O) XH-, -8 (= O) ₂ XH- and -XNS (= O) XH-, and the other is selected from the group consisting of a single bond and -CH ₂ -; A is selected from the group Ν; X, Υ and Ζ are CH; t1 has a value of 1; one of K _1-2 is and the other is selected from the group consisting of H, E, C1, Br, I, ΝΗ ₂ and C _1-10 alkoxy; Ό _{1 is} selected from the group consisting of a single bond, -ΝΗ- and -O-; Ό ₂ represents —C (K _b1 ) (K _b2 ) -, wherein said K _b1 and K _{b2 are} independently selected from the group consisting of H and C _1-10 alkyl; Ό _{3 is} selected from the group consisting of -Ν (Κ _ά4 ) -, -С (= ОА (Ка ₄ ) -, -№ (Ка ₄ ) С (= О) -, -8 (= О) ₂ - and - 8 (= O) A (Ka ₆ ) -, wherein said KB4 and KB6 are independently selected from the group consisting of H and K02; K _{4 is} selected from the group consisting of H, C _1-10 alkyl and C _1-10 heteroalkyl, wherein said C _1-10 alkyl and C _1-10 heteroalkyl are optionally substituted with K ₀₁ , where said C _1-10 heteroalkyl contains 1 or 2 heteroatoms or heteroatomic groups, each of which is independently selected from the group consisting of Ν, O, 8, C (= O) NN, C (= O) and -8 (= O) ₂ ; η is 1, 2, 3 or 4; or any of K _b1 and 1 < _b 2 in the same Ό ₂ , two Ό ₂ , K ₄ and one Ό ₂ , or K ₄ and Ό _{3 are} attached together to the same carbon atom or hetero atom to form one or two 3-, 4-, 5- or 6-membered carbocyclic rings or a 3-, 4-, 5- or 6-membered heterocyclic ring, wherein said heterocyclic ring contains 1, 2 or 3 heteroatoms or heteroatomic groups, each independently selected from the group consisting of Ν, O, 8, C (= O) XH, C (= O) and -8 (= O) ₂ ; K _{01 is} selected from the group consisting of E, C1, Br, I, OH, 8H and Co ₂ ; Co _{2 is} selected from the group consisting of C _1-10 alkyl, C _1-10 alkanoyl and C _1-10 alkylsulfonyl, wherein said Co _{2 is} optionally substituted with K ₀₀₁ , and Co _{01 is} selected from the group consisting of E, C1, Br, I, OH, ΝΗ ₂ and methoxy; and in any of the above cases, the amount of K ₀₁ or Ko ₀₁ each independently is 0, 1, 2 or 3. 2. The compound represented by formula (I), or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ε is selected from the group consisting of C _1-6 alkyl and C _3-6 cycloalkyl, or Ε is selected from the group consisting of hLLLL where O _1-5 are C (K ₃ ); O _{6 is} selected from the group consisting of -C (K ₃ ) (K ₃ ) - and -8-; none or one of O _7-9 represent Ν, and others represent C (K ₃ ); and all other variables have values as defined in claim 1. 3. The compound represented by formula (I), or a pharmaceutically acceptable salt thereof according to claim 2, wherein Ε is selected from the group consisting of methyl, all of which are optionally substituted with 1, 2 or 3 K3. 4. The compound represented by formula (I), or a pharmaceutically acceptable salt thereof according to claim 3, wherein Ε is selected from the group consisting of and methyl, all of which are optionally substituted with 1, 2 or 3 halogen atoms, ΝΗ ₂ and C _{1- 3} alkyl. 5. The compound represented by formula (I), or its pharmaceutically acceptable salt according to claim 3, where Ε is selected from the group consisting of - 61 032642 6. The compound represented by formula (I), or its pharmaceutically acceptable salt according to claim 1, where the ring formed between any of K ^ ₁ and K ^ ₂ in the same Ό ₂ , two Ό ₂ , K ₄ and one Ό ₂ or K ₄ and Ό ₃ is selected from the group consisting of all of which are optionally substituted with 1 or 2 halogens, OH, ΝΗ ₂ , C _1-3 alkyl, trifluoromethyl, trifluoroethyl, ^ = Ο) ΝΗ ₂ or C _{1- 3} alkylC (= O). 7. The compound represented by formula (I), or its pharmaceutically acceptable salt according to claim 1, where the ring formed between any of K ^ ₁ and K ^ ₂ in the same Ό ₂ , two Ό ₂ , K ₄ and one Ό ₂ or K ₄ and Ό ₃ , selected from the group consisting of 8. The compound represented by formula (I), or its pharmaceutically acceptable salt according to claim 1, where one of K ₂ represents and K ₁ selected from the group consisting of Η, E, C1, ΝΗ ₂ and OS _1-3 alkyl . 9. The compound represented by formula (I), or its pharmaceutically acceptable salt according to any one of claims 1 to 7, where one of K _1-2 selected from the group consisting of about - 62 032642 and the other is selected from the group consisting of H, P, C1, Ν ^, methoxy, ethoxy and propoxy. 10. The compound or its pharmaceutically acceptable salt, where the specified compound is selected from the group consisting of - 63 032642 1500 Solvent control, PO, (DO, p = 5 VKM120, 30 mg / kg, PO, O.O. p = 5 Compound 11.8 mg / kg, PO, (DO, p = 5 Days of treatment